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However, your cells mostly consist of water and so do all the tissues and organs in your body. So, how do they maintain their shape and what gives them structural and mechanical support? As a prior article noted it is the cell’s cytoskeleton (microtubules, microfilaments and intermediate filaments) that give it shape and structural and mechanical support. And it is the connective tissue, consisting of cells (mostly fibroblasts) that secrete a gel-like ground substance and protein fibers, that crisscross through it, which provide your body’s tissues and organs with structural and mechanical support. The ground substance and protein fibers are called the extracellular matrix (ECM) which is the non-cellular component of connective tissue. In fact, different types of connective tissue provide different types of support. In the human body this runs from solid bones, to softer and more elastic cartilage, to high tensile strength ligaments and tendons, to the delicate web-like laced spider-like networks (bubble wrap) that supports most of its organs and passageways. It all depends upon the different types of cells which secrete different types of ground substance and the density and material qualities of the different protein fibers running through it. But the ECM does much more than just provide the body’s tissues and organs with structural and mechanical support. It also affects cell signaling, migration, growth, proliferation, differentiation and survival, all of which regulates tissue morphology, development, homeostasis and function. The first four articles in this series outlined how the ECM manages these functions through its main components, collagen and elastin fibers (ECS-12), the gel-like ground substance made of water, glycoaminoglycans (GAGs) and proteoglycans (PGs) (ECS-13), glycoproteins (GPs), and cell surface receptors like integrins (ECS-14), and growth factors (GFs), cytokines, chemokines, matrikines, enzymes and their inhibitors, (ECS-15) (see Figure 1).
The last article explained how all of the components of the ECM (and more) work together in a coordinated fashion to accomplish wound healing The Extracellular Matrix - Part 5. This sixth, and final article, will take a brief look at embryonic development. It will start with an overview of what components are required for tissue and organ development, take a deep dive into how this plays out practically by looking at spinal cord development and then apply this to the whole. Keep in mind, that we are supposed to believe that an unguided process, like natural selection acting on random variation, was responsible for the presence of each of the components and what they in combination do for the body. In The Beginning Immediately after formation of the zygote, the maternal control phase of embryonic development begins. The human ovum contains large stores of maternal mRNAs, proteins, ribosomes, tRNAs, metabolites, and cell-cycle regulators. Together, these drive the early cleavage divisions, control DNA replication, regulate early gene expression, support cellular metabolism, and provide the molecular machinery required for the initiation of development. They also contribute to the earliest patterning events and establish developmental competence for later embryonic signaling. Thus, in humans, the ovum mainly provides the machinery that allows development to begin, whereas much of the detailed body-patterning information emerges later through embryonic gene expression, gene regulatory networks, and intercellular signaling. Morphogens and More Once embryonic control is established, development proceeds through the continual integration of morphogen gradients, local cell-cell signaling, gene regulatory networks (GRNs), temporal history (the signals a cell has previously experienced), epigenetic state, and physical forces. Signaling inputs and physical cues are interpreted by GRNs, which regulate gene expression and thereby determine cell behavior, differentiation, and tissue organization. A morphogen is a diffusible signaling molecules produced in a localized region that form a concentration gradient across a developing tissue. Different morphogen concentrations activate different gene-expression programs in responding cells. During embryonic development, cells are often exposed to multiple morphogens simultaneously and at different times. Cells interpret both the concentration and combination of these morphogenic signals through their receptors and intracellular signaling pathways, which ultimately regulate transcription factors (TFs) and gene regulatory networks (GRNs) that determine cell fate and behavior. By doing so, morphogens provide positional information, allowing cells to determine where they are located within the developing embryo. There are approximately 10-15 major morphogen or developmental signaling families that together comprise more than 100 individual signaling molecules. Some of the major families include Hedgehog (e.g., Sonic Hedgehog, SHH), Bone Morphogenetic Proteins (BMPs), Wingless/Integrated (WNTs), Fibroblast Growth Factors (FGFs), Transforming Growth Factor-β (TGF-β) family members, Notch ligands, and Retinoic Acid (RA). These signaling systems are repeatedly reused throughout embryonic development in different combinations, concentrations, locations, and time windows to generate diverse developmental outcomes. For example, Hedgehog proteins (especially SHH) help pattern the neural tube, spinal cord, forebrain, limbs, and craniofacial structures; BMPs help regulate dorsal neural tube development, bone formation, cartilage development, kidney formation, and heart development; WNT signaling influences body-axis formation, neural development, limb development, skin and hair follicle formation, and stem-cell maintenance; FGFs regulate limb bud outgrowth, brain development, heart formation, lung branching, and mesoderm induction; TGF-β family members help control gastrulation, mesoderm formation, left-right asymmetry, heart development, and connective tissue formation; Notch signaling is important for neural progenitor maintenance, blood-cell development, vascular development, somite (body segment) formation and intestinal stem-cell regulation; and Retinoic Acid helps pattern the hindbrain, spinal cord, limbs, heart, lungs, and many other developing organs. Local cell-cell signaling is important because not all developmental signals diffuse over long distances as morphogens. Many cells communicate directly with their immediate neighbors through membrane-bound ligands and receptors. Examples include Notch-Delta signaling, which helps regulate cell-fate decisions and maintain stem-cell populations; Eph-ephrin signaling, which helps establish tissue boundaries and guides cell migration and axon growth and cadherin-mediated cell adhesion, which allows cells to recognize and attach selectively to neighboring cells. This form of signaling provides highly localized developmental information and helps refine tissue boundaries, coordinate differentiation, and maintain stem-cell niches. Because the signal requires cell-cell contact, only adjacent cells can respond. Whereas morphogens primarily tell a cell where it is, local cell-cell signaling tells a cell who its neighbors are and helps coordinate its behavior with the surrounding cells. GRNs are the intracellular decision-making circuits that determine which genes a cell expresses. A GRN consists primarily of interacting TFs, regulatory DNA elements (enhancers, promoters, silencers), and their target genes. Signals received from morphogens and cell-cell interactions are ultimately interpreted by GRNs, which then determine cell fate and behavior. In essence, if morphogens tell a cell where it is and cell-cell signaling tells it who its neighbors are, GRNs decide what the cell should become and how it should behave. The human genome encodes approximately 1,600 TFs. However, any particular cell type typically uses only a small subset of these, often a few dozen to perhaps a hundred key TFs organized into a specific GRN. These TFs activate and repress one another through complex feedback and feed-forward loops, creating stable patterns of gene expression that can persist long after the original developmental signal has disappeared. Consequently, GRNs act as a form of developmental memory that helps lock cells into stable identities such as neurons, muscle cells, cardiomyocytes, or blood cells. Temporal history refers to the fact that a cell's developmental response depends not only on its current signals but also on the signals it has experienced previously. The same morphogen concentration can produce different outcomes depending on the cell's developmental history. Prior signaling events may alter receptor expression, activate or repress TFs, modify chromatin accessibility (see below), or establish feedback loops within GRNs. Consequently, embryonic cells often respond to developmental signals in a sequence-dependent manner. Development therefore depends not only on where a cell is, but also on the path it took to get there. Temporal history provides developmental context, allowing cells to interpret current signals in light of their previous experiences. Epigenetics refers to molecular mechanisms that regulate gene expression without changing the DNA sequence itself. These mechanisms influence which genes are accessible for transcription and which remain silent. Some epigenetic components include DNA methylation, histone modifications (acetylation, methylation, phosphorylation, etc.), chromatin-remodeling complexes, higher-order chromatin organization, and regulatory non-coding RNAs. Together, these mechanisms determine how accessible particular genes are to TFs. Cells with identical DNA can therefore exhibit dramatically different patterns of gene expression because they possess different epigenetic states. In practical terms, epigenetics determines which parts of the genome are currently available for use and which remain inaccessible. Physical forces generated by neighboring cells, the ECM, and tissue movements continuously affect embryonic cells. These mechanical cues ultimately influence cell shape, migration, proliferation, polarity, and differentiation. Major mechanical influences include cell-cell tension, compression, stretching, shear forces, and ECM stiffness. Cells detect these forces through, among others, integrins, the cytoskeleton, and mechanosensitive ion channels. Mechanical information can then directly alter gene expression and often works together with morphogen signaling to shape developing tissues. Thus, mechanical forces inform cells about their physical environment and help ensure that developmental programs remain coordinated with tissue architecture. To summarize, morphogens tell a cell where it is, local cell-cell signaling tells a cell who its neighbors are, temporal history tells a cell what it has experienced previously, epigenetics determines which genes a cell is currently permitted to use, mechanical forces tell a cell about its physical environment and GRNs integrate all of this information and determine what the cell should become and how it should behave. IOW, all of these inputs ultimately converge on GRNs, which convert positional, local, historical, epigenetic, and mechanical information into specific patterns of gene expression that determine cell fate, tissue organization, and body structure. Practical Example (Spinal Cord Development) Applying the summary above to spinal cord development; morphogens tell neural tube cells where they are, local cell-cell signaling tells them who their neighbors are, temporal history tells them what signals they have previously encountered, epigenetics determines which developmental genes are accessible, mechanical forces provide information about tissue shape and growth, and gene regulatory networks (GRNs) integrate all of these inputs to determine cell fate and behavior. More specifically, the ventral neural tube is exposed to a high-to-low gradient of SHH secreted first by the notochord and later by the floor plate. SHH binds to its cell-surface receptor, initiating intracellular signaling that prevents proteolytic conversion of GLI proteins into transcriptional repressors and instead promotes formation of transcriptionally active GLI proteins that regulate gene expression. Cells exposed to high SHH concentrations maintain high GLI activity and express TFs such as Nkx2.2, producing the most ventral progenitor domains, whereas cells exposed to intermediate or low SHH concentrations activate different TF combinations such as Olig2 or Pax6, producing progressively more dorsal progenitor populations. Thus, cells interpret SHH concentration through quantitatively different levels of GLI-mediated gene expression. Simultaneously, the dorsal neural tube is exposed to opposing gradients of BMPs and WNTs released from the roof plate. BMPs bind to BMP receptors on the cell surface and activate intracellular SMAD signaling pathways, leading to formation of activated SMAD transcriptional complexes within the nucleus that regulate expression of dorsal-patterning genes. Different BMP concentrations and exposure times promote expression of distinct TF combinations that specify progressively different classes of dorsal interneurons. Local cell-cell signaling further refines these broad morphogen-defined regions. Notch signaling between adjacent progenitor cells influences whether cells remain proliferative neural progenitors or begin neuronal differentiation. Neighboring cells also exchange signals that sharpen boundaries between progenitor domains and stabilize cell identities. Temporal history is critical because neural progenitors do not simply respond to current morphogen levels. Their prior exposure to SHH influences future responsiveness. For example, prolonged SHH exposure can activate TFs that are not induced by brief exposure, allowing both concentration and duration of signaling to contribute to cell identity. A cell exposed to moderate SHH for a long period may activate a different transcriptional program than a cell exposed to the same concentration briefly. Epigenetic mechanisms determine which genes can respond to these signaling pathways. Chromatin accessibility, histone modifications, and DNA methylation influence whether GLI proteins, SMAD complexes, and other TFs can access their target genes. Thus, two cells receiving identical extracellular signals may activate different genes if their chromatin states differ. Mechanical forces also contribute. As the neural tube bends, closes, elongates, and expands, cells experience changes in tension, compression, cell shape, and attachment to the ECM. Mechano-sensitive pathways communicate these physical conditions to the nucleus, influencing proliferation, polarity, migration, and differentiation. Ultimately, all of these inputs converge on interacting GRNs composed of TFs such as Nkx2.2, Olig2, Pax6, Pax7, and many others. These TFs activate some genes while repressing competing developmental programs. The resulting cross-repressive network converts continuous SHH, BMP, Wnt, Notch, temporal, epigenetic, and mechanical signals into discrete progenitor domains, producing motor neurons ventrally, multiple classes of interneurons dorsally, and ultimately the highly organized architecture of the spinal cord. The key idea is that SHH and BMP gradients do not directly "make" motor neurons or interneurons. Rather, they establish different levels of GLI and SMAD activity, which alter GRNs. Those GRNs then execute the developmental decisions that create the patterned structure of the spinal cord. Putting It All Together (Zygote From a developmental biology perspective, the transition from a zygote to a full-term infant involves the coordinated activity of numerous signaling pathways, intracellular signaling systems, TFs, and GRNs. Although enormously simplified, some of the major stages are as follows.
Viewed as a whole, development can be understood as a hierarchy of information-processing systems. Morphogens establish positional information, cell-cell signaling refines local decisions, intracellular pathways such as GLI, SMAD, β-catenin, MAP kinase, Notch, and receptor tyrosine kinase signaling transmit information to the nucleus, transcription factors interpret those signals, and GRNs integrate them into stable developmental programs. The result is the progressive emergence of increasingly specialized cells, tissues, organs, and body systems from a single fertilized cell. One striking feature is that the same signaling pathways are reused repeatedly throughout development. SHH, BMP, WNT, FGF, Notch, TGF-β, and Retinoic Acid signaling appear at multiple stages and in multiple organs. Rather than having a unique signaling system for each tissue, development largely relies on reusing a relatively small number of signaling pathways in different combinations, concentrations, locations, durations, and developmental contexts, with GRNs interpreting these signals to generate tissue-specific outcomes. AI-generated Evolutionary “Explanation” Evolutionary biologists generally explain the origin of such developmental systems as the cumulative result of random genetic variation (mutation, gene duplication, recombination, and other sources of genetic change) filtered over long periods of time by natural selection. According to this view, developmental signaling pathways, transcription factors, receptors, cell-adhesion systems, and GRNs were not assembled all at once but arose through numerous incremental modifications of pre-existing biological components. Genes and pathways that improved survival or reproductive success were preferentially retained, while less advantageous variants were eliminated. Over many generations, repeated modification, duplication, co-option, and integration of these components are proposed to have produced the highly interconnected developmental systems observed in modern animals. Thus, within the standard evolutionary framework, the complexity of embryonic development is explained as the cumulative outcome of undirected genetic variation acted upon by natural selection over vast spans of time. Questions
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