https://phys.org/news/2025-04-early-embryos-flexibility-dna.html

"An international research team led by Helmholtz Munich has, for the first time, provided a detailed insight into how the spatial organization of genetic material is established in the cell nucleus of early embryos within the first hours after fertilization. Surprisingly, embryos demonstrate a high degree of flexibility in responding to disruptions in this process.

"The study, now published in Cell, reveals that no single master regulator controls this nuclear organization. Instead, multiple redundant mechanisms ensure a robust and adaptable nuclear architecture, allowing embryos to correct errors in the initial organization of their nucleus.

"When the egg and sperm fuse, a comprehensive reorganization of DNA begins within the nucleus. Epigenetics plays a crucial role in this process, regulating gene activity through chemical modifications on DNA and its associated proteins.

***

"'Previously, it was not known whether a single central mechanism controlled nuclear organization after fertilization. Our results show that after fertilization, multiple parallel regulatory pathways control nuclear organization, reinforcing each other."

"To decipher the mechanisms of this reorganization, the researchers conducted a mid-scale perturbation screening in mouse embryos. To map epigenetic changes in early embryos, they employed state-of-the-art molecular biology techniques. The analyses uncovered multiple redundant regulatory mechanisms involved in nuclear organization.

***

"To map epigenetic changes in early embryos, they employed state-of-the-art molecular biology techniques. The analyses uncovered multiple redundant regulatory mechanisms involved in nuclear organization. (my bold)

"Furthermore, the experiments revealed that—contrary to previous assumptions—gene activity is not strictly determined by nuclear positioning. "The position of genes within the nucleus did not always correlate with their activity," explains Mrinmoy Pal, first author of the publication and doctoral researcher at the Institute of Epigenetics and Stem Cells.

"Some genes remained active despite shifting to a nuclear region traditionally considered inactive, while similar relocations in other cases led to a drastic reduction in gene expression. "This challenges the classical model of nuclear organization and genome function," Pal concludes.

"Even more surprising was the finding that embryos can self-correct disruptions in nuclear organization, even after the first division of the fertilized egg. If nuclear organization was disrupted prior to the first cell division, it could get restored during the second cell cycle. This suggests that early embryos are not only resilient but also possess mechanisms to compensate for errors in their initial nuclear organization.

"The researchers discovered that this process is regulated by epigenetic marks inherited from the maternal egg cell. If these maternal signals are disrupted, the embryo can activate alternative epigenetic programs to eventually restore correct nuclear organization that might not originate from the mother. This indicates that embryos can utilize different starting points for their development to prevent developmental defects."

Comment: Note my bold. Multiple redundant regulatory mechanisms are required to follow the underlying blueprint of the new individual for exact reproduction.

https://www.the-scientist.com/just-curious-how-do-embryos-know-how-fast-to-develop-72560

"Different species live their lives at remarkably different paces. This biological tempo is apparent even before birth: In just three weeks, a fertilized egg can turn into a baby mouse, whereas in elephants, this process can take up to 22 months. While these different trajectories have long been appreciated, the biological mechanisms that set the pace during development remain incompletely understood.

"Body size does play a role, but it’s not the only important factor. In fact, the pace of embryogenesis—the period of development during which most of the internal organs form—doesn’t scale with body weight. For example, in cattle, this phase lasts about 40 days, but in the comparatively diminutive marmoset, it is closer to 80 days.

***

"The core segmentation clock gene, called hairy and enhancer of split 7 (HES7), is a transcription repressor, explained Ebisuya. “If HES7 protein is expressed, it starts repressing its own expression, and therefore the HES7 protein level goes down,” she said. “Then the repression is released, and the expression level goes back up. It's a one-factor negative feedback loop.” Using a stem cell-derived model so that temperature and other extracellular factors could be controlled, Ebisuya found that the period of this genetic clock was species-specific. For instance, it was 122 minutes in mice, 236 in a rhinoceros, and 388 in a marmoset.

***

"But what controls the pace of the segmentation clock? The answer is complicated. The HES7 feedback loop—and thus the periodicity of the clock—is governed by the speed of multiple biochemical processes, including transcription, translation, intron removal, and mRNA and protein degradation. Ebisuya wanted to investigate cellular metabolism as a potential modulator of species-specific tempo. “But the problem with metabolism is that the definition is not so clear,” she said. Indeed, her recent paper suggested pharmacologic inhibition of different metabolic processes had distinct effects on the kinetics of different sections of the HES7 feedback loop.

“'My current working hypothesis,” said Ebisuya, “is that rather than a single, common global modulator of species-specific tempo, each species combines different metabolic modulators to achieve its own tempo.'”

Comment: her comment makes good sense. Each species will have its own clock of development. HES7 will be used as specifically required everywhere.

https://phys.org/news/2025-01-cues-cells-harness-electric-fields.html

"As an embryo grows, there is a continuous stream of communication between cells to form tissues and organs. Cells need to read numerous cues from their environment, and these may be chemical or mechanical in nature. However, these alone cannot explain collective cell migration, and a large body of evidence suggests that movement may also happen in response to embryonic electrical fields. How and where these fields are established within embryos was unclear until now.

"'We have characterized an endogenous bioelectric current pattern, which resembles an electric field during development, and demonstrated that this current can guide migration of a cell population known as the neural crest," highlights Dr. Elias H. Barriga, the corresponding author who led the study published in Nature Materials.

***

"The neural crest is an essential part of the embryo, and this region of cells forms the bones of our face and neck, as well as parts of the nervous system. Dr. Barriga and colleagues found that cells of the neural crest are directed by internal electric fields during development, much like drivers follow the signals of a traffic warden.

"The group discovered that through this process, known as electrotaxis, cells can sense direction from electric fields generated inside the embryo and move accordingly. This observation had been previously limited mostly to the study of cultured cells, but has now been demonstrated within a developing embryo. But an important question remained unanswered: How are the cells interpreting these currents and translating them into directional movement?

"To answer this question, Dr. Barriga and his team identified an enzyme known as voltage-sensitive phosphatase 1 (Vsp1) found in neural crest cells. Due to the versatile structure of Vsp1, it seemed capable of both sensing and transducing electrical signals. To confirm that Vsp1 is required for electrotaxis, the researchers created a defective version of the enzyme and showed that collective electrotaxis was impaired in cells injected with this copy.

***

"Contrary to expectations, Vsp1 did not appear to be relevant for movement itself, but instead could specifically convert electric current gradients into directional and collective migration. This is a unique observation, as most enzyme sensors are required for movement itself, making it difficult to study their role in guiding direction.

"Going one step further, the authors also proposed how the electric fields may form: through mechanical stretching of a region known as the neural fold. As the cells in this region stretch, this causes activation of specific ion channels, resulting in a voltage gradient. Then, when cells encounter this gradient, Vsp1 transforms the electrical signals into a directional cue, telling the cells which way to go, and collective cell migration results.

"This is the first experimental evidence to suggest that electric fields emerge along the path where neural crest cells migrate, and to explain their mechanism of origin. These discoveries highlight a valuable contribution that bioelectricity provides during embryonic development. By advancing our knowledge of electrotaxis within a living animal, this research opens new possibilities for mimicking developmental processes in the lab, with accuracy greater than ever before.

***

"'In a broader perspective, we have now introduced another player into the intricate process of tissue morphogenesis" says Dr. Barriga. "The question is now, how does this fit into already established frameworks of mechanical and chemical cues during embryogenesis?".

"Beyond development, similar mechanisms might also exist during wound healing and cancer progression. Understanding how electric fields guide cell migration could even inspire potential novel strategies in tissue engineering and regenerative medicine. However, further research is required to expand on the role of electric fields in cellular behavior, and increase our understanding of the physics behind living systems."

Comment: the use of electric fields to control growth of tissue is a fascinating addition to the mechanical and other forces recognized at work in forming a whole organism. Not desvoloped by step-by-step changes from random mutations. Strong evidnece of design.

https://phys.org/news/2024-10-gut-genetics-physics-embryonic.html

"Genes are the control panel for an embryo morphing from a ball of cells into organs, muscles, and limbs, but there's more involved than just genetics. There's also physics—the shaping of tissues by flows and forces from cellular activity and growth.

***

"The Developmental Cell paper, led by...Hasreet Gill, shows how a set of developmental instructions called Hox genes dictate gut formation. For the study, Gill and colleagues traced the gut development of a chicken embryo as a model organism; Hox genes are also found in humans and all other vertebrates.

***

"Gill's study built on previous work looking at how Hox genes are involved in organ differentiation. The set of genes, highly conserved throughout animal evolutionary history, was the subject of the 1995 Nobel Prize when they were recognized for their role in segmenting a fruit fly's body.

"Gill and colleagues discovered that measurable mechanical properties of the tissues that make up the large and small intestines of a chick embryo are directly involved in how they arrive at their final shapes. For example, the tissues that form the villi located in the small intestine, she found, have different stiffness parameters than those that shape the inside walls of the large intestine, which form larger, flatter, more superficial folds.

***

"Gill's team repeated the experiment while running physical tests on the mechanical characteristics of the different parts of the gut, considering things like wall stiffness, growth rate, and tissue thickness. They found that the HoxD13 gene in particular regulates the mechanical properties and growth rates of the tissues that eventually lead to the large intestine's final shape. Other, related Hox genes may define those same properties for the small intestine.

"Crucially, they also illuminated the role of a downstream signaling pathway called TGF Beta, which is controlled by Hox genes. By tuning the amount of TGF beta signaling in their embryos, they could switch the shapes of the different gut regions. Seeing the importance of this pathway, long known to be involved in fibrotic conditions, was an important basic-science step toward fully understanding gut development in a vertebrate system.

***

"The complementary PNAS paper, co-led by Gill and Yin, showed how geometry, elastic properties, and growth rates control various mechanical patterns in different parts of the gut.

"'We focused on how mechanical and geometric properties directly affect morphologies, especially more complicated, secondary buckling patterns, like period-doubling and multiscale creasing-wrinkling patterns," said Yin, an expert in theoretical modeling and numerical simulations of active and growing soft tissues.

"Added Mahadevan said, "These studies allow us to begin probing aspects of the developmental plasticity of gut development, especially in an evolutionary context. Could it be that natural variations in the genetic signals lead to the variety of functional gut morphologies that are seen across species? And might these signals be themselves a function of environmental variables, such as the diet of an organism?"

***

"Morphogenesis is driven by forces arising from cellular events, tissue dynamics, and interactions with the environment," Yin said. "Our studies bridge the gap between molecular biology and mechanical processes." (my bold)

Comment: the bold above is a synopsis of the whole process. Obviously a band of cells as it grows exerts physical forces. The molding of any embryo uses control of the types of cells to be grown as one step, and somehow patterns the forces that develop to help in shaping the embryo into its final form. Just magical. And beyond natural development of the process.

https://www.sciencedaily.com/releases/2024/10/241010142527.htm

"Embryo development starts when a single egg cell is fertilized and starts dividing continuously. Initially a chaotic cluster, it gradually evolves into a highly organized structure. An international team of researchers...has provided new insights into the process, emphasizing the critical role of both chaos and order.

***

"The international team of researchers has built a comprehensive atlas of early mammalian morphogenesis -- the process of an organism developing shape and structure -- analyzing how mouse, rabbit, and monkey embryos develop in space and time. Based on this atlas, they see that individual events such as cell divisions and movements are highly chaotic, yet the embryos as a whole end up looking very similar to one another. With this dataset, they propose a physical model that explains how a mammalian embryo builds structure from chaos.

***

"...an embryo's shape is highly complex, making it difficult to determine what it means for two embryos to be similar or different. The scientists discovered that they could effectively approximate the full complexity of the structure of an embryo simply by studying the configurations of the cell-to-cell contacts. "We think that we can derive most of the important details about the morphology of an embryo by understanding the arrangements of cells or knowing which cells are physically connected -- similar to connections in a social network. This approach significantly simplifies data analysis and comparisons between different embryos," says Corominas-Murtra.

***

"The model shows that physical laws drive embryos to form a specific morphology shared among mammals.

"By destabilizing most cell arrangements except a few selective ones that lower the surface energy of the embryo, physical interactions between cells can guide the formation toward a defined shape. In other words, cells tend to stick more and more together and this seemingly simple process actually drives the embryo through successive rearrangements to the most optimal packing. It's like embryos solve their own Rubik's cube. (my bold)

"The results provide a detailed look at how the development of mammalian embryos is governed by variability and robustness. Without chaos, there is no structure; one needs the other. Both are essential parts of what constitutes 'normal' development. "We're finally starting to have tools to analyze the variability of morphogenesis, which is crucial to understanding the mechanisms of developmental robustness," Hannezo summarizes. Randomness seems to be a primary force in the generation of complexity in the living world.

"By gaining more knowledge of what normal looks like, scientists also gain insights into abnormalities. This can be very helpful in areas, such as disease research, regenerative medicine, or fertility treatments."

Comment: The hyperbole of 'chaos' in the article is overreach for emphasis. The embryo is following a blueprint which involves some chaotic-like appearances. The process is highly controlled.

https://www.the-scientist.com/the-first-two-cells-in-a-human-embryo-contribute-dispropo...

"In the early stages of human embryonic development, a zygote divides into two identical totipotent cells that eventually become eight cells. Cell fate decisions begin to differentiate this totipotent population into specific lineages, giving rise to the blastocyst. At least, this has been the working model. Now, a new study published in Cell suggests this may not be the full story.

“'They are not identical,” said Magdalena Zernicka-Goetz, a developmental and stem cell biologist at the California Institute of Technology and the University of Cambridge and study coauthor. “Only one of the two cells is truly totipotent, meaning it can give rise to body and placenta, and the second cell gives rise mainly to placenta.” The findings help elucidate what happens during the earliest periods in development. (my bold)

***

"To understand this process better, Zernicka-Goetz set out to investigate if human embryonic development resembled that of mice. She and her team first tracked cell lineage from the two-cell stage; they injected mRNA for green fluorescent protein (GFP) fused to a membrane trafficking sequence into one of the two cells of the zygote. Thus, they could determine the contribution of each cell to the development of two early structures: the trophectoderm (TE) that becomes the placenta and the inner cell mass (ICM) that eventually produces the epiblast, or fetal tissue, and the hypoblast, or the yolk sac.

"When they tracked GFP expression, the team found that one population of cells dominated in either the ICM or the TE, but that this imbalance was greatest in the ICM. Within the ICM, progeny from one clone at the two-cell stage dominated the population of the epiblast, while the composition of the hypoblast was split between cells of the two originating clones. “This means that at the two-cell stage we have a cell fate bias of these two cells, but it's not a deterministic process,” said Zernicka-Goetz.

"To further investigate the cell contribution to the ICM, the researchers labeled DNA and actin and, starting at the eight-cell stage, tracked cellular positions after division using live cell imaging. Asymmetric cell divisions (ACD) involve cells that intrude into the growing cell mass rather than remain on the surface, and these interior cells contribute to the ICM. The team observed that while ACD were less common overall, their composition resembled that of the ICM.

“'I was always interested in how cells decide their fate,” Zernicka-Goetz said. In the mouse developing embryo, she previously demonstrated a bias at the two-cell stage: one cell contributed more to fetal tissue and the other to the placenta.

“We know so little about the very early stages of human development,” said Nicolas Plachta, a developmental biologist at the University of Pennsylvania who was not involved with the study.

"In mice, the two-cell stage clone that contributed more to the ICM divided faster than the second cell, so the team studied whether or not this pattern applied to human embryonic development. The team studied movies of actively dividing embryos and determined that in most of the embryos, one cell at the two-cell stage divided faster, and its progeny also inherited this feature. The team also noticed that the first cell to undergo ACD was one of these fast-dividing cells.

“'This is the first study to do some nice cell tracking in a human embryo at those early stages,” said Platcha. However, he noted that the inherent variability in human embryos compared to established mouse models makes it difficult to draw conclusions in this research area. This is further complicated by the limited number of zygotes available for research because clinics typically preserve embryos at later developmental stages.

Comment: What is amazing is just two cells are packed with information for the development of fetus and placenta. It all unfolds step by step with many reproductive cellular divisions but also mechanical forces shape the resultant organs. Not by chance.

https://phys.org/news/2024-02-simple-recipe-limb.html

"The team found that a combination of just three proteins—Prdm16, Zbtb16, and Lin28a—is necessary and sufficient to turn certain non-limb-forming stem cells into limb-forming ones. A fourth protein, Lin41, speeds the process along.

"Part of a family called gene transcription factors, these proteins activate a handful of genes inside certain cells in embryonic tissue known as mesenchyme, the researchers revealed. This change in gene activity is what transforms the cells into limb progenitor cells, the team showed.

"Limb progenitor cells then bud out where a limb will form and provide a framework for the future arm, leg, wing, or fin.

***

"It also remains to be discovered which other ingredients need to be added for limb progenitor cells to mature into the limb's connective tissues, such as tendons, ligaments, and the middle layer of skin.

***

"'We tested a lot of conditions to see what the cells like and what they don't like. We found they are particularly finicky about stiffness," said Lee. "The only limitation we've found so far is that the cells grow so well that they fill up the containers we use, which is a good problem to have."

"Developmental and evolutionary biologists and regenerative medicine scientists are now better positioned to answer questions such as:

"The roles the three gene transcription factors play in other organ systems and organisms.

"What factors contribute to later limb development, such as fingers and toes.

"What distinguishes fore- and hind limb development.

"How these insights can inform efforts to regrow different organs to treat injury or disease.
"It's important to understand the basic properties of cells that have a therapeutic value," said Lee. "Culturing and maintaining limb progenitor cells and directing them to more specific lineages is fundamentally important for the long-term goal of replenishing cells in the clinic."

***

"'Understanding and harnessing mammalian limb progenitors is a first step toward considering mammals as models for regenerating amputated limbs, as an alternative to the amphibians and other limb-regenerating critters being studied today," said Tabin."

Comment: humans playing God, recoding DNA successfully.

https://phys.org/news/2024-02-pituitary-gland-embryonic-insights-growth.html

"Situated at the base of the brain, this pea-sized organ, also known as the hypophysis, plays a central role in maintaining body metabolism. Interfacing between the brain and the blood, it can be described as the control center of the endocrine system, which releases hormones into the bloodstream.

***

"The structure of the pituitary, which contains two separate lobes that serve different physiological functions, has been highly conserved throughout evolution, meaning that fish, mouse and human pituitary glands are largely similar. For many years researchers took great interest in a fundamental question: Where do the two lobes originate during embryonic development?

"The early embryo consists of three primary cell layers, from which the entire body ultimately arises: The endoderm (the inner layer), the mesoderm (middle layer) and the ectoderm (outer layer). Until now, the generally accepted view was that the cells making up each of the two lobes of the pituitary originated from separate embryonic subdivisions of the ectoderm.

"The frontal, or anterior lobe, which releases six major hormones—including the thyroid-stimulating and growth hormones—was thought to originate solely from the early embryo's exterior tissue layer, the oral ectoderm. The posterior lobe, which releases two major brain-derived hormones—oxytocin, a regulator of reproduction and behavior, and vasopressin, which controls various aspects of body fluid balance—was thought to originate from the neural ectoderm, a tissue that eventually also forms the nervous system.

***

"In line with the prevalent dogma, she expected the frontal lobe of the fish's pituitary to contain only cells with genetic labels from the early embryo's oral ectoderm, and the posterior lobe, from the embryo's neural ectoderm. Instead, she found that some of the cells in the frontal lobe were descendants of the embryo's neural ectoderm.

"'This finding contradicted the idea that the two parts of the pituitary gland have entirely separate origins," Levkowitz says. "There had been hints in research by other scientists that these origins might be mixed, but before our study, no one had produced the smoking gun."

***

"By identifying the exact molecular signatures of the major cell types in the pituitary, the project also led to an additional finding: Previously unknown cross-talk between different cells belonging to the frontal and posterior parts of the gland.

"The researchers discovered that certain cells in the posterior lobe, called pituicytes, influence the development of hormone-producing cells in the frontal lobe. The pituicytes, a subtype of the astroglia—star-shaped cells of the nervous system—were known to facilitate the release of oxytocin and vasopressin hormones from the posterior pituitary lobe.

"'Our finding was a surprise—in addition to their previously known function, pituicytes play a role in the development of the frontal pituitary," says Chen."

Comment: as the master central controller of our endocrine system, the fact that some of the
anterior lobe of the pituitary has a neural origin suggests that fibers from the brain, probably the hypothalamus, are monitoring the pituitary actions. This was designed. Imagine all the very many fortuitous cooperative mutations to achieve this result.

https://www.cell.com/cell/fulltext/S0092-8674(24)00044-8?dgcid=raven_jbs_aip_email

"Summary
Microglia (MG), the brain-resident macrophages, play major roles in health and disease via a diversity of cellular states. While embryonic MG display a large heterogeneity of cellular distribution and transcriptomic states, their functions remain poorly characterized. Here, we uncovered a role for MG in the maintenance of structural integrity at two fetal cortical boundaries. At these boundaries between structures that grow in distinct directions, embryonic MG accumulate, display a state resembling post-natal axon-tract-associated microglia (ATM) and prevent the progression of microcavities into large cavitary lesions, in part via a mechanism involving the ATM-factor Spp1. MG and Spp1 furthermore contribute to the rapid repair of lesions, collectively highlighting protective functions that preserve the fetal brain from physiological morphogenetic stress and injury. Our study thus highlights key major roles for embryonic MG and Spp1 in maintaining structural integrity during morphogenesis, with major implications for our understanding of MG functions and brain development."

Comment: This demonstrates that the morphogenesis of the embryotic brain is corralled into shape by microglia, whose normal role is as macrophages for cleanup and protection.

https://www.sciencedaily.com/releases/2024/01/240109121139.htm

"sea squirt oocytes (immature egg cells) harness friction within various compartments in their interior to undergo developmental changes after conception.

***

"Sea squirts or ascidians in particular are very unusual: after a free-moving larvae stage, the larva settles down, attaches to solid surfaces like rocks or corals, and develops tubes (siphons), their defining feature.

"Although they look like rubbery blobs as adults, they are the most closely related invertebrate relatives to humans.

"Especially at the larval stages, sea squirts are surprisingly similar to us.

"Therefore, ascidians are often used as model organisms to study the early embryonic development of vertebrates to which humans belong.

***

"The findings suggest that upon fertilization of ascidian oocytes, friction forces play a crucial role in reshaping and reorganizing their insides, heralding the next steps in their developmental cascade.

"Oocytes are female germ cells involved in reproduction. After successful fertilization with male sperm, animal oocytes typically undergo cytoplasmic reorganization, altering their cellular contents and components.

"This process establishes the blueprint for the embryo's subsequent development.

"In ascidians, for instance, this reshuffling leads to the formation of a bell-like protrusion -- a little bump or nose shape -- known as the contraction pole (CP), where essential materials gather that facilitate the embryo's maturation.

***

"The scientists microscopically analyzed fertilized ascidian oocytes and realized that they were following very reproducible changes in cell shape leading up to the formation of the contraction pole.

The researchers' first investigation focused on the actomyosin (cell) cortex -- a dynamic structure found beneath the cell membrane in animal cells.

"Composed of actin filaments and motor proteins, it generally acts as a driver for shape changes in cells.

"'We uncovered that when cells are fertilized, increased tension in the actomyosin cortex causes it to contract, leading to its movement (flow), resulting in the initial changes of the cell's shape," Caballero-Mancebo continues.

"The actomyosin flows, however, stopped during the expansion of the contraction pole, suggesting that there are additional players responsible for the bump.

***

"...they came across the myoplasm, a layer composed of intracellular organelles and molecules (related forms of which are found in many vertebrate and invertebrate eggs), positioned in the lower region of the ascidian egg cell.

"'This specific layer behaves like a stretchy solid -- it changes its shape along with the oocyte during fertilization," Caballero-Mancebo explains.

During the actomyosin cortex flow, the myoplasm folds and forms many buckles due to the friction forces established between the two components.

"As actomyosin movement stops, the friction forces also disappear.

"'This cessation eventually leads to the expansion of the contraction pole as the multiple myoplasm buckles resolve into the well-defined bell-like-shaped bump," Caballero-Mancebo adds.

"The study provides novel insight into how mechanical forces determine cell and organismal shape. It shows that friction forces are pivotal for shaping and forming an evolving organism."

Comment: the push-pull of forces is just one mechanism. There are electrical influences, changes in molecular shapes, the actions of enzymes driving reactions, etc. We see the driving forces but do not know how DNA really controls the actions.

https://www.the-scientist.com/news-opinion/how-soft-or-stiff-substrates-direct-stem-cel...

"Mesenchymal stem cells (MSCs) hold a lot of potential. They have the capacity to differentiate into bone and cartilage as well as muscle and fat. They are also critical to regenerating tissues, but how they go from stem cell to fat cell or bone cell is not completely understood.

"Now, researchers revealed that the stiffness of the environment affects the fate of MSCs via changes in expression of a gene that regulates myosin contractility called tropomyosin-1 (TPM1). The findings demonstrated how extracellular clues inform stem cell responses in tissue regeneration, and add another clue to what drives heterogenous responses to mechanical cues.

"The mechanical environment—how elastic the underlying substance is—influences what type of cells MSCs go on to become. Less elastic, stiff substrates promote differentiation into bone, while soft substrates favor fat. In the lab, researchers mimic the mechanical environment by culturing cells on hydrogel matrices that have measured elasticities. Yet, even when cultured under the exact same conditions, not all cells follow the environment’s lead.

***

"Sequencing revealed gene expression changes that reflected soft matrices supporting differentiation toward fat and stiff matrices promoting differentiation into bone. But not all cells tracked along the expected route. For example, some cells cultured on soft matrices showed decreased expression of genes associated with early fat cell development, but increased expression of genes associated with early bone formation. Altogether, the single-cell transcriptomes partitioned into nine subpopulations with distinct sensitivities to the mechanical environment and differentiation capacities.

"The researchers then looked for genes with expression that responded to matrix elasticity. Of nearly 4,000 genes expressed per cell, TPM1 stood out. TPM1 ranked 19 out of the top 100 matrix-dependent genes, indicating that TPM1 expression might influence MSC cell-fate decision-making in response to the mechanical environment.

***

“'We know cells respond to the mechanical environment and that influences outcome, but how that happens remains unclear. They’re identifying a key player in the process,” said Jan Lammerding, a biomedical engineer at Cornell University in Ithaca, New York, who was not involved in the new work.

"The findings underscore the significance of heterogeneous cellular responses to mechanical signaling. “If we want to really mimic the physiological context, we cannot cover our eyes in front of mechanical signals,” Buxboim said."

Comment: going from embryo to a formed individual is a complex 3-D process in which mechanical processes influence stem cell activity. This study offers a glimpse into the natural process.

https://www.sciencealert.com/cells-inside-living-embryos-use-tiny-tubes-to-mail-package...

"In a study made available on the pre- peer review archive bioRxiv, researchers in France witnessed long, thin tubes shuttling cargo between cells inside zebrafish embryos.

"'This study marks the first demonstration of functional tunneling nanotubes in a living embryo," the authors report.

"Cells were first seen extending tendrils to other cells in 2004. Since then, cancer cells have been caught using these 'nanotubular highways' like straws to suck up the energy powerhouses known as mitochondria from healthy cells.

"In petri dish experiments, tunneling nanotubes that stretch up to 100 micrometers in length seem to provide an important intercellular transport service for chemicals, messenger RNA, proteins, organelles, viruses, and bacteria. These nanotubes could play a role in the development of cancer, Alzheimer's disease, HIV and SARS-CoV2.

"Observing mini-postal systems at work in a petri dish is one thing, but it's another thing entirely to verify the same network exists inside a complex, 3D structure like a living animal. Inside multicellular living things, there's so much stuff packed in together that the slender fibers can easily get lost in the noise.

"'Cells are very densely packed, which makes it impossible to observe intercellular structures if all of the cells are labeled," the researchers write.

"The French researchers overcame this difficulty by tracking the growth of tendrils inside rapidly developing, transparent zebrafish embryos.

***

"Tunneling nanotubes were distinguished from other tendrils as they formed uninterrupted threads that were longer than 5 micrometers.

"Once the embryo reached its gastrula stage, around 35 percent of the labeled cells were connected by tunneling nanotubes.

"The movement of soluable materials and bulkier items is a "defining feature of open-ended tunneling nanotubes", the researchers write.

"To confirm this trait was present in the fish embryos, the researchers injected the cells with a Dendra2 protein that is too big to pass through other intercellular channels (such as jap junctions between neighboring cells). They then observed signs of the cumbersome protein passing from one cell to another.

"The team also injected cells with a mRNA dye that would label mitochondria from one cell and then watched these mitochondria being transported through a nanotube to a far away cell."

Comment: Amazing. Communication must help in building the embryo.

https://www.sciencedaily.com/releases/2023/09/230927154920.htm

"Becoming a full-fledged organism out of a handful of cells, complete with functioning tissues and organs, is a messy yet highly synchronized process that requires cells to organize themselves in a precise manner and begin working together.

"This process is especially dramatic in the heart, where static cells must start beating in perfect unison.

***

"In a study conducted in zebrafish, the team discovered that heart cells start beating suddenly and all at once as calcium levels and electrical signals increase. Moreover, each heart cell has the ability to beat on its own, without a pacemaker, and the heartbeat can start in different places.

***

"'The heart beats about 3 billion times in a typical human lifetime, and it must never take a break," said co-senior author Adam Cohen, professor of chemistry and chemical biology and of physics at Harvard.

***

"Using fluorescent proteins and high-speed microscope imaging, the researchers captured changes in calcium levels and electrical activity in heart cells of developing zebrafish embryos. To their surprise, they discovered that all the heart cells abruptly transitioned from not beating to beating -- characterized by simultaneous spikes in calcium and electrical signals -- and immediately began beating in sync.

"'It was like somebody had flipped on a switch," Cohen described.

"Further experiments revealed that for each heartbeat, one region of the heart fires first, initiating a wave of electricity that rapidly flows through the rest of the cells and prompts them to fire.

"Interestingly, the heartbeats started from different spots in different zebrafish, suggesting that there's nothing unique about the cells that fire first. This finding was counterintuitive because cells in adult hearts behave differently.

***

"'The heart first learns how to keep pace without a clock, and individual cells first learn to cooperate without agreeing on what their roles are," Jia added. "It is very important for the heartbeat to be regular, but it is organized very quickly at the start of life from what seems to be a total mess."

"Developing zebrafish offer a convenient model for studying the heart because they are transparent, grow quickly -- developing a heartbeat in only 24 hours -- and can be imaged by the dozen. However, Megason thinks the same developmental process may be conserved across species, including humans."

Comment: the heart is made up from unusual muscles, has amazingly different cell parts from filamentously thin valves, specialized firing points, and conduction bundle cells to transmit electric firing signals. Blood flow is arranged in one direction. The first hearts appeared in the Cambrian explosion along with the first brains. Designed special organs requiring the existence of a designer.

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/18_august_2023/4124...

"The yolk sac (YS) generates the first blood and immune cells and provides nutritional and metabolic support to the developing embryo. Our current understanding of its functions derives from pivotal studies in model systems, and insights from human studies are limited. Single-cell genomics technologies have facilitated the interrogation of human developmental tissues at unprecedented resolution. Atlases of blood and immune cells from multiple organs have been greatly enhanced by focused, time-resolved analyses of specific tissues.

" To characterize the functions of the human YS, we performed single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) on the YS and paired embryonic liver. After integration with external datasets, our reference comprised 169,798 cells from 10 samples spanning 4 to 8 postconception weeks PCW) or Carnegie stages (CS) 10 to 23. A repertoire of two-dimensional (2D) and 3D imaging techniques provided spatial context and validation. We compared the products of two hematopoietic inducible pluripotent stem cell (iPSC) culture protocols against our reference.

"We determined that YS metabolic and nutritional support originates in the endoderm and that the endoderm produces coagulation proteins and hematopoietic growth factors [erythropoietin (EPO) and thrombopoietin (THPO)]. Although metabolic and coagulation protein production was conserved among humans, mice, and rabbits, EPO and THPO production was observed in humans and rabbits only.

"We reconstructed trajectories from the YS hemogenic endothelium to early hematopoietic stem and progenitor cells (HSPCs). Using transcriptomic signatures of early and definitive hematopoiesis, we parsed YS HSPCs into myeloid-biased early HSPCs and lymphoid and megakaryocyte-biased definitive HSPCs. Human embryonic liver remained macroscopically pale before CS14, when hematopoietic cells first emerge from the aorta-gonad-mesonephros (AGM) region. Tracking hemoglobin (Hb) subtypes led us to conclude that initial erythropoiesis is YS restricted. By contrast, in mice, Hb subtypes suggested two waves of pre-AGM erythropoiesis, including maturation in the macroscopically red embryonic liver.

"Before CS14, monocytes were absent and macrophages originated from HPSCs via a premacrophage cell state. After CS14, monocytes emerged and a second, monocyte-dependent differentiation trajectory was reconstructed. A rare subset of TREM2+ macrophages, with a microglia-like transcriptomic signature, was present after CS14. The iPSC system optimized for macrophage production recapitulated the two routes to macrophage differentiation but did not generate the diversity of macrophages (including TREM2+ macrophages) observed in developing tissues.

"CONCLUSION: Our study illuminates a previously obscure phase of human development, where vital functions are delivered by the YS acting as a transient extraembryonic organ."

Comment: The developing fertilized egg ends up by creating an invasive placenta with its own plethora of functions. Not by chance.

https://medicalxpress.com/news/2023-08-neuronal-migration-neurons-room-growth.html

"Researchers at the Instituto Gulbenkian de Ciência (IGC, Oeiras) and Max Planck Institute of Cell Biology and Genetics (MPI-CBG, Dresden) identified a new mechanism that exposes some of the multitasking abilities embryos need to build a functional retina.

***

"To function properly, organs require a precise number of cells and a functional architecture, which are established during embryogenesis. Embryos are proficient multitaskers; they grow, and acquire shape and functional architecture all at once.

"Despite much research on embryo development, scientists do not yet fully grasp how embryos orchestrate all these different tasks in space and time to ensure the formation of healthy organs. This was the central question of the study led by Caren Norden (group leader) and MauricioRocha-Martins (postdoctoral researcher). The research team, that also involved computer scientists, used cutting-edge technology to explore how the vertebrate retina copes with the challenges of growing profusely while, at the same time, remodeling tissue architecture.

"The retina of zebrafish embryos and human retinal organoids—mini retina-like structures in a dish grown from human cells—were used as model systems because they both offer unique advantages due to their small size and high translucency, allowing real-time observation of tissue organization and growth. Advanced microscopy techniques, such as light-sheet microscopy and state-of-the-art image restoration based on deep learning, provided unprecedented insight into the cellular behaviors involved.

"The researchers observed that an entire population of neurons, photoreceptors, temporarily relocates away from the zone of the tissue where they reside and must fulfill their function. This active movement creates space for incoming progenitor cells that divide in this area and thereby produce more cells that later contribute to the neuronal retina.

"Blockage of the movements of photoreceptors leads to congestion, forcing progenitor cells to divide in wrong place which in turn causes tissue malformation. Thus, by transiently moving away, neurons avoid interference with progenitor cells to ensure harmonious organ development.

"To Mauricio Rocha-Martins, the first author of the study, "This is a curious migration phenomenon, in which neurons move away just to then move back, ending up where they started. It highlights that neuronal migration, as opposed to what was previously believed, does not only move neurons to their correct location but can also play a direct role in the coordination of organ development."

"The implications of this research extend beyond the field of retinal development. Simultaneous growth and acquisition of functional architecture is a hallmark of most developing organs; the new findings offer the possibility to investigate whether other developing organs employ similar strategies.

"Moreover, it is known that defects in neuronal migration can cause severe brain malformations in humans. The findings that failed migration of neurons can have deleterious consequences beyond the positioning of neurons points to the importance of examining the interactions between cells to fully understand the causes of human developmental disorders."

Comment: the controls of this necessary purposeful movement is not yet known. The whole process of embryo formation did not happen by chance.

https://www.sciencedaily.com/releases/2023/07/230721113116.htm

"It has been known for some time that the genome of a newly fertilized egg cell is inactive and has to be woken up, said Richard Schultz, research professor at the University of California, Davis, School of Veterinary Medicine and a corresponding author on the paper. This step is called zygote genome activation.

***

"For the resetting or awakening process to occur, the embryo needs to start transcribing genes from its DNA into messenger RNA that are in turn translated into proteins. The first genes transcribed will activate other genes, implementing the program that will allow the embryo to develop into a complete mouse (or human). The identity of those first master-regulator genes has been unknown until now.

***

"RNA polymerase II (Pol II) is the enzyme that transcribes DNA to RNA. But Pol II by itself is a dumb enzyme, Schultz said. Other genes, called transcription factors, are needed to instruct Pol II so that it transcribes the "correct" genes at the right time.

"In the early 2000s, Schultz had the insight that those first transcription factors would be found among dormant maternal messenger RNAs in the egg cell. Dormant maternal messenger RNAs are unique to oocytes because the newly synthesized messenger RNA is not translated as it is in somatic cells. As the oocyte matures to become an egg, these dormant maternal messenger RNAs are translated into proteins that then execute their function. Schultz realized that the information to start zygote genome activation would be in a dormant messenger RNA from the mother that would encode a master transcription factor.

***

"Schultz's lab identified a large family of genes called OBOX as likely candidates. The family consists of 8 genes, OBOX1-8. Based on their expression profiles during early development, OBOX1, 2, 3, 4, 5, and 7 were likely candidates. They began working with Wei Xie at Tsinghua University, Beijing to narrow down the candidates.

***

"Most interesting, and unanticipated, was that the function of these OBOX genes was highly redundant: a knockout of one could be replaced by another. That redundancy has likely evolved because the transition is so important, Schultz said. In addition, the researchers found that the OBOX genes function by facilitating Pol II locating to the correct genes to begin zygote genome activation.

"In mice, genome activation occurs at the two-cell stage. In human embryos, it occurs later, when the embryo has gone through a couple of rounds of division to form eight cells. An open question is how conserved this process is across species, i.e., are OBOX-like genes involved in genome activation in humans. The work also has implications for understanding how embryonic stem cells are reprogrammed so that they can develop into any tissue of the body."

Comment: the step to sexual reproduction undoubtedly facilitated evolution, but added huge complexity to the reproductive process of simple cell splitting. The early zygotic kick-start is a series of events that is irreducibly complex and must be designed all at once to be effective. Without this design the species will not reproduce.

https://phys.org/news/2023-07-key-function-tight-junctions-embryo.html

"As a human embryo grows, a set of molecules directs cells as they multiply and take on specific identities and spatial positions within the embryo. In one crucial step known as gastrulation, these signaling molecules guide a single layer of embryonic stem cells to form three layers of distinct cell types that will later become different parts of the body.

"Now, researchers in the iPS Cell Research Center at Gladstone Institutes have shown that tight junctions between cells may play a critical role in gastrulation in human embryos.

***

"Gastrulation sets a foundation for the development of the entire human body. Researchers have found ways to recreate a simplified version of this fundamental process in a dish by starting with a layer of induced pluripotent stem cells, or iPS cells—adult cells that have been reprogrammed to mimic embryonic stem cells, meaning they can differentiate to become any cell type in the body.

"Then, scientists add a protein called BMP4, a key signaling molecule in gastrulation, which causes the cells in the dish to begin to form the three layers of cells found in the embryo. However, since all of the cells appear to receive the same BMP4 signal, it has been unclear why some transform into one cell type while others become different cell types.

***

"Yamanaka, Vasic, and their team found that growing the cells in a less-confined space allowed the tight junctions to assemble consistently. When they added BMP4 to the unconfined cells, they got their "aha" moment: only cells at the edge of the cluster received enough BMP4 to activate molecular pathways that would nudge them to become different layer cell types.

"'Tight junctions between adjacent cells seem to make them impervious to signals from BMP4," Vasic says. "But the edge cells don't have a buddy to form tight junctions with on their outer side, which means they are getting the strongest cues from BMP4."

***

"'We showed that removing the tight junctions made all the cells respond to BMP4," says Yamanaka, who is also a professor of anatomy at UC San Francisco, as well as director emeritus and professor at the Center for iPS Cell Research and Application (CiRA), Kyoto University, in Japan. "This suggests that tight junctions block cells from responding to signals in gastrulation models, and more fundamentally, that the structure of cells is very important to how they receive differentiation signals."

"'Broadly speaking, this study demonstrates how perturbations to innate properties of iPS cells can modulate their sensitivity to extracellular cues and alter their cell fate trajectory," says Todd McDevitt, Ph.D., former senior investigator at Gladstone and a senior author of the study. "This principle could be a game changer for unlocking the potential of iPS cells to produce more homogeneous populations of differentiated cells for therapeutic applications.'"

Comment: these studies with cells are the only way we can interpret how the embryo is controlled in development. The appearance of a designed process is obvious.

https://phys.org/news/2023-06-scientists-earth-earliest-animals-evolved.html

"Lacking bones, brains, and even a complete gut, the body plans of simple animals like sea anemones appear to have little in common with humans and their vertebrate kin. Nevertheless, new research from Investigator Matt Gibson, Ph.D., at the Stowers Institute for Medical Research shows that appearances can be deceiving, and that a common genetic toolkit can be deployed in different ways to drive embryological development to produce very different adult body plans.

"It is well established that sea anemones, corals, and their jellyfish relatives shared a common ancestor with humans that plied the Earth's ancient oceans over 600 million years ago. A new study from the Gibson Lab, published in Current Biology, illuminates the genetic basis for body plan development in the starlet sea anemone, Nematostella vectensis. This new knowledge paints a vivid picture of how some of the earliest animals on earth progressed from egg to embryo to adult.

***

"Most contemporary animals, from insects to vertebrates, develop by forming a head-to-tail series of segments that assume distinct identities depending on their position. Within a given segment, there is a further axis of polarity that informs cells whether they are at the front or back of the segment. Collectively, this is referred to as segment polarization.

"Shuonan He, Ph.D., a former predoctoral researcher from the Gibson Lab, uncovered genes involved during development of the sea anemone, Nematostella vectensis, that guide the formation of segments and others that direct segment polarity programs strikingly similar to organisms higher up the evolutionary tree of life, including humans.

"'The significance is that the genetic instructions underlying the construction of extremely different animal body plans, for example, a sea anemone and a human, are incredibly similar," said Gibson. "The genetic logic is largely the same." (my bold)

"This new study builds upon a 2018 study published in Science from the Gibson Lab that showed that sea anemones have an internal bilateral symmetry early in development with eight radial segments. The study demonstrated that Hox genes—master development genes that are crucial for human development—act to delineate boundaries between segments and likely had an ancient role in segment construction.

"The team's latest finding explores how segments form and what accounts for differences in their identities. Using spatial transcriptomics, or the differences in gene expression between segments, the team discovered hundreds of new segment-specific genes. These include two crucial genes that encode transcription factors that govern segment polarization under the control of Hox genes and are required for the proper placement of sea anemone muscles.

"The astonishing diversity of organisms on Earth can be compared to the assembly of Legos. "Whether you construct a dinosaur, a sea anemone, or a human, many of the core genetic building blocks are largely the same despite drastically different animal forms," said Gibson.

"This is the first time that scientists have evidence of a molecular basis for segment polarization in a pre-bilaterian animal. While extensively studied in bilateral species like fruit flies and humans, the idea that cnidarian animals possess segmentation was unexpected. Now, the team has evidence that these segments are also polarized.

"'This provides further evidence that investigating a broad diversity of animals can have direct implications for understanding general principles, including those which apply to human biology," said Gibson. "Going one step further, by understanding the logic of sea anemone development and comparing it to what we see in vertebrates, we can also extrapolate back in time to understand how animals likely developed hundreds of millions of years ago.'"

Comment: this is direct evidence experimentation by God did not occur. It was all obviously planned from the beginning. Note my bold.

https://phys.org/news/2023-05-pro-viral-human-protein-critical-embryo.html

"A new study led by scientists at Uppsala University and INRAE/Université Paris-Saclay has discovered that the pro-viral host protein ZC3H11A plays a critical role in maintaining embryo viability during early development. The study has uncovered a previously unknown function of ZC3H11A in the intricate process of embryonic growth and highlights its impact on development.

"With over twenty thousand genes in the human body, the physiological functions of many genes remain elusive. A previous study from the same team identified ZC3H11A (abbreviated as ZC3) as a pro-viral protein because it is required for efficient growth of several human nuclear-replicating viruses such as HIV.

"...In the current study, the team has uncovered an additional function of ZC3 during a specific time-point in early embryo growth in mice. Interestingly, upon deleting ZC3 in adult mouse tissues, no apparent defects were observed. This finding indicates that ZC3 possesses distinct roles depending on the developmental stage.

"The current study demonstrated that ZC3 plays a pivotal role in regulating the expression of metabolic genes crucial for the metabolic changes that occur in embryos around implantation. The disruption or absence of ZC3 results in complete lethality of mouse embryos and it is likely that inactivation of this gene is lethal in other mammals including humans. This finding emphasizes the indispensable nature of ZC3 in orchestrating the metabolic processes essential for embryo survival and development.

***

"...The results of this study revealed a surprising outcome, as complete inactivation of ZC3 in mouse tissues did not exhibit any noticeable effects on cell growth or viability. The fact that ZC3 depletion in adult tissues did not result in any noticeable clinical consequences suggests that an anti-viral therapy based on inactivation of ZC3 may not have significant side effects.

"'ZC3H11A stands out as one of the many highly conserved genes across vertebrates but with a poorly described function. This study shed light on the functional significance of ZC3 as one of the factors critical for normal embryo development," says Leif Andersson, Professor of Functional Genomics at Uppsala University. "The fact that ZC3 does not appear to be critical for cellular growth after birth but for replication of multiple medically important viruses makes it an interesting target for the development of new anti-viral therapies.'"

Comment: ZC3 is a specific molecule with specific effects during gestation. Chance wevolution is not likely to produce such a result.

https://phys.org/news/2023-05-chinmo-youth-gene.html

"A new study published on eLife and led by the Institute for Evolutionary Biology (IBE, CSIC-UPF) and the IRB Barcelona, has revealed that the Chinmo gene is responsible for establishing the juvenile stage in insects. It also confirms that the Br-C and E93 genes play a regulatory role in insect maturity. These genes, which are also present in humans, act as a promoter and as a suppressor, respectively, of cancerous processes.

"The results of the research, which was carried out with the fruit fly Drosophila melanogaster and the cockroach Blatella germanica, reveal that these genes have been conserved throughout the evolution of insects. Therefore, it is believed that they could play a key role in the evolution of metamorphosis.

"Insects that undergo complete metamorphosis, such as flies, go through the following three stages of development: the embryo, which is formed inside the egg; the larva (juvenile stage), which grows in several phases; and the pupa, which is the stage that encompasses metamorphosis and the formation of the adult organism.

"Previous studies had discovered that the Br-C gene determines pupal formation in insects. In 2019, the same IBE team that has led this study described the essential function of E93 to complete metamorphosis in insects and initiate the maturation of the tissues that go on to form the adult. However, the gene responsible for determining the juvenile stage was unknown until now. This study has now identified the Chimno gene as the main precursor of this stage in insects.

"By deleting the Chinmo gene in Drosophila specimens, the scientists observed that these insects progressed to the pupal stage without completing the juvenile stage, moving to the adult stage early. These findings thus confirm that Chinmo is essential for juvenile development.

***

"...the study concludes that the Chinmo gene has to be inactivated for Drosophila to progress from the juvenile to the pupal stage and to carry out metamorphosis successfully. Likewise, it confirms that the sequential action of the three genes, namely Chinmo, Br-C, and E93, during the larval, pupal, and adult stages, respectively, coordinate the formation of the different organs that form the adult organism.

***

"'Understanding the molecular functioning of cell growth can help to better comprehend cancer processes. Healthy cells grow, differentiate, and mature. In contrast, cancer cells grow uncontrollably, do not differentiate, and fail to mature. So determining the role of Chinmo, Br-C, and E93 may be key to future clinical research," says Dr. Jordi Casanova, an IRB Barcelona researcher and co-author of the study.

"The study shows that while Chinmo is an oncogenic precursor because it promotes tissue growth and prevents differentiation, C-Br and E93 serve as tumor suppressors by activating tissue maturation.

***

"'Analyzing the function of these genes in different species of insects allows us to observe how evolution works. The observation that Chinmo function is conserved in insects as evolutionarily separated as flies and cockroaches gives us clues as to how metamorphoses originated," explains Dr. David Martin, a researcher at the IBE (CSIC-UPF) who co-led the study."

Comment: this study, like most others, shows the genetic continuity in evolution of controlling genes. But this is the surface. We still don't know how genes create their controls.