One of the aims of developmental biology is to discover the developmental origins of morphological variation. 11 Genomic regulatory systems drive embryonic development of the body plan 17 Many studies have revealed that genes encoding transcription factors and signalling molecules are critical controllers of pattern formation and cell fate specification during development. 18
The process of morphogenesis, which can be defined as an evolution of the form of an organism, is one of the most intriguing mysteries in the life sciences. The discovery and description of the spatial-temporal distribution of the gene expression pattern during morphogenesis, together with its key regulators, is one of the main recent achievements in developmental biology. Nevertheless, gene expression patterns cannot explain the development of the precise geometry of an organism and its parts in space. First, we suggest that the geometry of the organism and its parts is coded by a molecular code located on the cell surfaces in such a way that, with each cell, there can be associated a corresponding matrix, containing this code. As a particular model, we propose coding by several types of oligosaccharide residues of glycoconjugates. 7
To understand the major trends in animal diversity and if the various kinds of morphology are due to evolution, we must first understand how animal form is generated.
Morphology is the product of development, the process through which a single fertilized egg cell gives rise to an entire organism. Given that the DNA of (most) all cells in an animal is identical, how do different cells acquire the unique morphologies and functional properties required in the diverse organs and tissues of the body? We now understand that this process occurs through the selective expression of distinct subsets of the many thousands of genes in any animal’s genome in different cells. How genes are turned on and off in different cells over the course of animal development is an exquisitely orchestrated regulatory program. If morphological diversity is all about development, and development results from genetic regulatory programs, then is the origin of diversity directly related to genetic regulatory programs? Simply put, yes.
But to understand how diversity emerged, and if evolution is an adequate explanation, it must first be understood how the genetic regulatory mechanisms operate in development. What is the genetic toolkit of development and how does it operate to build animals? The foremost challenge for embryology has been to identify the genes and proteins that control the development of animals from an egg into an adult. Early embryologists discovered that localized regions of embryos and tissues possess properties that have long-range effects on the formation and patterning of the primary body axes and appendages. Based on these discoveries, they postulated the existence of substances responsible for these activities. A small fraction of all genes in any given animal constitute the toolkit that is devoted to the formation and patterning of the body plan and body parts.
Two classes of gene products with the most global effects on development are of special interest: families of proteins called transcription factors that regulate the expression of many other genes during development, and members of signalling pathways that mediate short- and long-range interactions between cells. The expression of specific transcription factors and signalling proteins marks the location of many classically defined regions within the embryo. These proteins control the formation, identity, and patterning of most major features of animal design and diversity.
Thom,1989 writes: We consider the concept of predetermination of a geometrical shape/form of living species to be the most appropriate. The matrix on a cell surface will be changed after each cell event according to the rule(s) dictated by the morphogenetic field of an organism. There is a connection between the morphogenetic code on the cell surface, cell motion law(s), and the geometry of an embryo. It is impossible to create a formalization of morphogenesis that is not based on a “deterministic concept”.
The developmental behaviour of a cell depends on the instructive signals from the surrounding space (area), and that different areas in a developing embryo contain precise instructions about the shape of corresponding organs. Because these features cannot be ignored in any model aiming to formalize the developmental process, we continue to exploit the morphogenetic field term in the framework of our model, as a possible convenient tool to describe the connection between biological information, encoded in the cells, and the realization of the geometrical form of a developing organism. A morphogenetic field is , in a mathematical sense, a “field” or a structure containing a space-time-dependent mechanism, which mediates the transformation of biological information, contained in cells, into the corresponding geometrical form of an organism in space-time; or, more precisely, into an instructive signal for a cell motion (cell event), depending on the position of this cell in the developing embryo. Thus, if the mathematical description of morphogenesis can be made in the framework of field theory, then it should be modified so as to consider the behaviour of the objects, whose nature depends on law(s) of coding of the information (i.e. geometrical information).
An overview of the various mechanisms that define body shape and form
Much attention has been focused on the processes that lead to determination of new structures during development. The major determinants of size and shape are more likely to involve just four major morphogenetic processes. These processes are
i) spatial regulation of mitotic density
ii) orientation of cell division
iii) biased rearrangements and intercalation of cells
iv) differential cell death
The orientation of division plays a key role in determining organ shape. In many tissues, cells can change relative positions by remodelling their contacts with neighbour cells. Biased orientation of the rearrangements results in tissue elongation, as is observed during the elongation of the Drosophila embryo. Differential cell death can result in a dramatic remodelling of tissue shape. For example, spacing between vertebrate digits is the consequence of inter-digital cell death. Moreover, an explanation of how variation in wing shape is generated requires a prior understanding of how these processes are regulated during development. 11
Signals regulating morphogenesis can be placed in two categories. On the one hand, morphogenetic cell behaviours are governed by extracellular signals secreted by cells, or by membrane-bound signals. For example, Bmp and Wnt-like proteins are generally involved in the control of cell proliferation and establish tissue fates, thus also playing a crucial role in cell differentiation. Because of their capacity to move from cell to cell, these proteins can establish concentration gradients pointing towards the source. Cells can sense the direction of such global gradients and translate these signals to establish their planar polarity (i.e, the polarity in the plane of the tissue) This is important because in many cases polarity defines the orientation of cell intercalations and divisions. In addition, the magnitude of that polarity has been proposed to regulate growth in some cases.
The second category of signals are mechanical forces, such as stretching or compression of a tissue, and the local growth environment, such as availability of nutrients. Mechanotransduction is the sensitivity of cells to mechanical signals. For example, the mammalian YAP/TAZ pathway, involved in growth regulation, is modulated by mechanical properties of the extracellular matrix. Forces extrinsic to epithelial cells can reorganize orientation patterns of cell rearrangements and divisions as well as cell fate, differentiation, and shape. Cell shape plays a special role in morphogenesis because it can directly modify tissue shape, and also regulates the morphogenetic processes as for example orientation of cell division and growth. Finally, there is growing evidence that cell death can be triggered by mechanical forces, as well as chemical signals.
The genetic toolkit
Toolkit genes are those whose products govern the construction of the house the toolkit that determines the overall body plan and the number, identity, and pattern of body parts. Toolkit genes have generally first been identified based on the catastrophes or monstrosities that arise when they are mutated.
1. The toolkit is composed of a small fraction of all genes Only a small subset of the entire complement of genes in the genome affects development in discrete ways.
2. Most toolkit genes encode either transcription factors or components of signalling pathways, Therefore, toolkit genes generally act, directly or indirectly, to control the expression of other genes.
3. The spatial and temporal expression of toolkit genes is often closely correlated with the regions of the animal in which the genes function.
4. Toolkit genes can be classified according to the phenotypes caused by their mutation. Similar mutant phenotypes often reflect genes that function in a single developmental pathway. Distinct pathways exist for the generation of body axes, for example, and for the formation and identity of fields.
5. Many toolkit genes are widely conserved among different animal phyla.
Most toolkit genes can be classified according to their function in controlling the identity of fields (for example, different segments and appendages), the formation of fields (for example, organs and appendages), the formation of cell types (for example, muscle and neural cells), and the specification of the primary body axes.
The second major category of toolkit genes encode proteins involved in the process of cell signalling, either as ligands, receptors for ligands, or components involved in the intracellular transduction of signals. At least seven major signalling pathways operate in the Drosophila embryo:
- the Hedgehog,
- Dpp/transforming growth factor-β (TGF-β),
- epidermal growth factor (EGF),
- fibroblast growth factor (FGF) signalling pathways
Field-specific selector genes
Another class of selector genes acts within specific developing fields to regulate the formation and/or the patterning of entire structures. Perhaps the best-known Drosophila field-specific selector gene is the eyeless (ey) gene. Flies that lack ey function can reach adulthood but never develop a compound eye. Molecular characterization of the ey gene revealed that it encodes a member of a particular homeobox gene family (Pax6 ), suggesting that the Ey protein acts as a DNA-binding transcription factor to regulate the expression of other genes. The ey gene is expressed in the developing eye field in the embryo, and in the larval eye imaginal disc, before the formation of the units (ommatidia) that make up the compound fly eye ( b below )
Field-specific selector genes
(a) Development of parts of the Drosophila adult depend upon the function of the ey (eyes), vg (flight appendages), and Dll (limbs) selector genes.
(b–d) These genes are expressed in both the embryonic primordia (left) and larval imaginal discs (right), which will give rise to these structures.
Compartment selector genes
Several genes have been identified in Drosophila that act within certain developing fields to subdivide them into separate cell populations, or compartments. The specification of cell fate is important for organizing cells into functional tissues during animal development. These compartment boundaries play a crucial role in tissue patterning and growth by stably positioning organizers. In Drosophila, the wing imaginal disc is subdivided into a dorsal and a ventral compartment. Cells of the dorsal, but not ventral, compartment express the selector gene apterous. Apterous expression sets in motion a gene regulatory cascade that leads to the activation of Notch signaling in a few cell rows on either side of the dorsoventral compartment boundary. Signalling between cells with different fates sets up a local source of organizers along compartments. Signalling molecules emanating from these organizer regions influence cell fate and growth of the entire tissue. Compartment boundaries thus serve as a reference line during pattern formation and growth.
For a flavour of the careful planning that goes into building even a relatively simple animal, let’s look briefly and sketchily at some of what’s been learned from studies of Drosophila development in recent years. The mother fly starts the process off by depositing in the egg, at the end that will become the head, a concentration of the instructions to make one kind of protein, called “bicoid,” and, at the end that will become the tail, a second kind of protein, called “nanos.” The bottom of the embryo is marked by the mother fly in a somewhat different way. The genes coding for proteins that specify the sides of the egg (front, back, top, bottom) are called “egg-polarity” genes. Critically, the proteins (or other proteins they affect) can stray in the egg, drifting away from their source; as they do they become more diffuse. As the egg initially divides into many cells, the high concentration of signal protein at one end of the fly turns on one set of control genes, the middle concentration turns on a different set of control genes in the middle portion of the embryo, and the lowest concentration activates a third set. Once the front, back, top, and bottom are marked (caution—it’s critical to keep in mind that the signal genes don’t actually form the structures found in those regions of the developing fly; they simply mark the location of a cell, like a surveying crew mapping out land for a construction project), positions are further refined with other control proteins. Several groups of proteins controlled by “segmentation genes” subdivide the embryo further. One group of about six so-called “gap genes” is switched on, marking chunks of segments; if one of these control proteins is defective, several neighbouring segments of the embryo will be missing. Oddly, another group of eight genes called “pair-rule genes,” affect alternate segments. If one of these is broken, a fly embryo will have only half its normal complement of segments. Finally, a group of ten “segment-polarity” genes helps differentiate each segment. Although in a normal fly the front of each segment looks a bit different from the back, in some segment-polarity mutants the two ends look the same.
The details can be mind-numbing, but the shape of the process is important: from egg-polarity genes to gap genes to pair-rule genes to segment-polarity genes, and we still aren’t ready to build the fly. The lifespan of all of the proteins coded by these control genes is brief, but they turn on genes for the more permanent Hox proteins, and thus permanently mark the position of cells in the developing animal embryo. Similar processes subsequently lay out compartments at finer and finer levels of the fly. For example, as a wing is built, the front, back, top, and bottom are marked by control genes, sometimes the same control genes that earlier marked various regions of the entire embryo. But now, working in a defined region of the developing animal, they mark the divisions and edges of the subcompartment. Remember, individual control genes don’t by themselves embody the instructions to build a wing—they just mark areas of the fly, and signal other genes to turn on or off. This short description leaves out many, many known details of the developmental process, including other means of cell-cell communication and the mechanics of how a signal is received and interpreted. But it at least gives a taste of how the body plan of a simple organism is set in motion. 16
What is a compartment boundary?
Within most proliferating tissues newborn cells can intermingle freely, and therefore occupy any position within the tissue. In some tissues, however, cells and their descendants are restricted to areas called compartments. The common border between two adjacent compartments is termed a compartment boundary. A key feature of compartment boundaries is that they involve a cell segregation mechanism. Cells from one compartment are kept segregated from cells of a neighbouring compartment leading to a straight boundary between compartments ( see picture below) Thus, a compartment boundary is a lineage boundary coupled to a cell-segregation mechanism. 9
Compartment boundaries are lineage borders linked to a cell segregation mechanism and serve to maintain the position and shape of organizers during growth of a tissue (exemplified by the Drosophila anteroposterior compartment boundary in the wing imaginal disc).
(a) A tissue is subdivided into two founder cell populations a that differ in the expression of a ‘selector’ gene [engrailed; ‘on’ (green) or ‘off’ (white)]. The state of expression of this selector gene becomes fixed and heritably perpetuated. During cell proliferation, cells from both populations tend to intermingle, partly because the position of newly emerging daughter cells is not restrained. The border between the descendants of the two founder populations is wiggly (left panel). By establishing a cell segregation system that can sort out ‘on’ cells from ‘off’ cells based on their lineage, the border between the two populations remains straight during cell proliferation (right panel). The lineage border linked to a cell segregation system is termed the compartment boundary (dashed line).
(b) The selector gene directs the expression of the short-range signalling molecule HH. The short-range signalling molecule moves to the adjacent ‘selector gene off’ cells, where it induces the expression of the morphogen DPP (red) in a few rows of cells, which act as an organizer. The morphogen moves away from its site of expression forming a graded distribution (red dots). The morphogen induces expression of target genes in a concentration-dependent manner leading to growth and patterning of the whole tissue. A wiggly border between ‘on’ and ‘off’ cells leads to an irregular and spatially unstable organizer incapable of directing precise patterning (left panel). In contrast, the compartment boundary between ‘on’ and ‘off’ cells leads to a straight and stable organizer and thereby to a precise patterning of the tissue (right panel). Furthermore, the position of the organizer is maintained during growth of the tissue.
Why are boundaries important?
During development, cells are ‘organized’ (i.e. instructed about their position and fate) by special, localized cell groups that secrete long-range signalling molecules. The exact positioning of these special cell groups, or organizers, is most critical for the patterning of tissues. Importantly, in growing tissues, cell proliferation leads to some cell mixing that might affect the spatial organization of the tissue. Nonetheless, the position and integrity of the organizer has to be maintained. There are at least two mechanisms by which this can be accomplished. The position of an organizer can itself depend on, and be maintained by, the influence of a more globally acting signalling molecule. Alternatively, an organizer can be positioned initially by a globally acting signalling system but then become independent of it. One important function of compartment boundaries is to maintain the position of organizers in growing tissues independent of globally acting signalling systems. This has been best illustrated for Drosophila wing development.
Like all appendages, the adult wing is derived from an imaginal disc, which is formed by invagination of the embryonic epidermis. The patterning process can be divided into several steps. In the first step, two adjacent groups of cells are selected according to their position along the anteroposterior axis of the embryo. Under the control of the embryonic patterning machinery, one, but not the other, cell group expresses a ‘selector’ gene.
In the case of the wing disc, this selector gene is engrailed and encodes a homeodomain transcription factor
Modulation of Phase Shift between Wnt and Notch Signaling Oscillations Controls Mesoderm Segmentation
How signalling dynamics encode information is a central question in biology. During vertebrate development, dynamic Notch signalling oscillations control segmentation b of the presomitic mesoderm (PSM). In mouse embryos, this molecular clock comprises signalling oscillations of several pathways, i.e., Notch, Wnt, and FGF signalling. We find that Wnt and Notch signalling are coupled at the level of their oscillation dynamics.
Segmentation of the body axis into a series of repeating units is a canonical strategy in morphogenesis, and evidence of this can be seen in the skeletal system of all vertebrates. Invertebrates (and even some insects), the developmental process of segmentation is characterized by the rhythmic and sequential addition of segments (called somites) to an elongating body axis and is regulated by an oscillatory mechanism -- the segmentation clock. 13
Typical image data before and after semantic segmentation
Combinatorial gene regulation by modulation of relative pulse timing
The pulsatile transcription factors Msn2 and Mig1 combinatorially regulate their target genes through modulation of their relative pulse timing. Regulation through relative signal timing is common in engineering and neurobiology, it functions also within the signalling and regulatory systems of the cell. In order to respond to environmental conditions, cells make extensive use of combinatorial gene regulation, in which two or more transcription factors co-regulate common target genes.
In order to respond to environmental conditions, cells make extensive use of combinatorial gene regulation, in which two or more transcription factors co-regulate common target genes. Most analysis of combinatorial regulation presumes that the concentrations of transcription factors in the nucleus are regulated in a continuous (non-pulsatile) manner.
According to Wiki, regulation is an abstract concept of management of complex systems according to a set of rules and trends. These types of rules exist in various fields of biology.14
Question: Is setting rules and trends, and management not something only done by intelligence? Can a mindless process like evolution set rules of regulation? In order to do so, is there not the before anything else, knowledge required of what has to be regulated, why, and how? Is not knowledge required to implement a functional regulation of biological systems, in order for them to be able to adapt to the environment for successful survival and development? For successful gene regulation, cells must know how to combine the right transcription factors, and how they find the right target genes ( interface compatibility of binding of the TF's to the right promoter sequence on the gene has to be pre-programmed.
Recent work has identified a large and growing list of transcription factors that activate in pulses. In such systems, a single pulse begins when many molecules of a given transcription factor are activated simultaneously, and ends when they are deactivated. Such pulses can occur repetitively, even under constant conditions. Pulsatile regulation has been observed in bacteria, yeast, and mammalian stress response and signalling pathways. In these systems, inputs typically modulate the pulse frequency, amplitude, and/or duration of individual transcription factors to regulate genes.
What functions could relative pulse timing modulation provide for the cell? One of the most fundamental concepts in combinatorial regulation is that cooperative interactions between transcription factors can increase their probability of simultaneous binding to a promoter, to implement cis-regulatory logic. Relative timing between signals plays many important roles throughout science and engineering. In neuroscience, the relative timing of action potentials at pre- and post-synaptic neurons controls the strength of synaptic connectivity through spike-timing-dependent plasticity. In communications, modulating the phase of a periodic signal relative to a reference signal is widely used to encode information. Cells seem to have evolved a related strategy by encoding aspects of the extracellular environment in the relative timing with which different transcription factors pulse. 15
Evolution seems to be an impotent mechanism to explain the origin of these ultrasophisticated coding and communication systems. The author mentions that " Cells evolved a strategy". This is clearly a teleological term. According to Wiki, Strategy (from Greek "art of troop leader; office of general, command, generalship") is a high-level plan to achieve one or more goals under conditions of uncertainty.
Pulsatile dynamics (both periodic and aperiodic) have been discovered in a growing list of central signalling and regulatory pathways. which are known to interact, or crosstalk, with one another.
The oscillation phase shift between Wnt and Notch signalling is critical for PSM segmentation. Dynamic signalling, i.e., the relative timing between oscillatory signals, encodes essential information during multicellular development.
Periodic segmentation of mesoderm into somites, the precursors of vertebrae, is controlled by a molecular clock, which in embryos includes ultradian (period ~2 hr) oscillations in Notch, Wnt, and FGF pathway activity. Notch signalling oscillations have been shown to be slightly phase shifted from one cell to the next along the anteroposterior axis in a spatially graded manner, and hence, oscillations generate periodic Notch activity waves that traverse the embryo from posterior to anterior. Moreover, unlike Wnt signalling oscillations, both the Notch and the FGF signalling oscillations depend on the transcriptional repressor Hes7, a core component of the segmentation clock, suggesting that oscillations of Notch and FGF signalling constitute outputs of a single clock mechanism. Between oscillatory Notch and FGF signals, it has been shown that Fgf signalling needs to be periodically shut off in newly forming segments within anterior presomitic mesoderm PSM to allow active Notch signalling to induce expression of the differentiation marker Mesp2 in this region. The differential regulation of individual oscillatory pathways may be critical for segmentation. There is a mechanism in which the local phase shift between oscillatory Wnt and Notch signalling in the presomitic mesoderm (PSM ) encodes information for mesoderm segmentation. Notch and Wnt signalling oscillations are coupled within the PSM, which is reflected in the ability to mutually synchronize each other upon entrainment of one signalling pathway.
My comment: Pulses activating transcription factors. Pulsatile regulation observed in bacteria, yeast, and mammalian signalling pathways. Pulse inputs modulating the pulse frequency, amplitude, and/or duration of individual transcription factors to regulate genes. Combinatorial regulation where cooperative interactions between transcription factors implement cis-regulatory logic. Cells using the strategy of modulating the phase of a periodic signal relative to a reference signal which is widely used to encode information. Pulsatile dynamics (both periodic and aperiodic) being part of a growing list of central signalling and regulatory pathways, interacting, or crosstalk, with one another. if that were not enough, cells use an oscillation phase shift between Wnt and Notch signalling, which is critical for segmentation during development. Dynamic signalling, i.e., the relative timing between oscillatory signals, encodes essential information during multicellular development.
One of the most remarkable properties of biological systems is the capacity of polarity formation, which also can be defined as the symmetry breaking capacity of the system. Polarity formation involves autonomous generation and assembling of highly specific geometrical structures, which can grow asymmetrically through different layers of complexity from nanostructures to micro- and macro structures. Therefore, self-organization is accompanied by the formation of geometrical structures with highly specific patterns and morphologies. The process also is called morphogenesis. Polarity formation in a self-organizing system requires a precise internal program and a source of energy to guide and enforce the progress of the process. Thus, self-organization only occurs through a dedicated preprogrammed process
Sets of morphogenetic markers on the cell surface can be written in the form of a matrix
We assume that the information regarding the geometry of an organism is contained on the cell surface, in the form of a code composed of biological molecules of a special type. Our prevailing assumption is that, most likely, such a code can consist of oligosaccharide residues of glycoconjugates on the cell surface. There are 12 types of monosaccharide that exist in oligosaccharide residues of glycoconjugates (with six of them being of hexose type), and there have been numerous observations indicating that these oligosaccharide residues are connected with the determination of cellular morphogenetic pathways. This information can be written in the form of a matrix, in which every element corresponds to the level of a certain type of oligosaccharide (or monosaccharide) in a given region (section) of the cell surface.
Morphogenesis, the shaping of an organism by cell movements, cell-cell interactions, collective cell behaviour, cell shape changes, cell divisions, and cell death, is a dynamic process on many scales, from fast subcellular rearrangements to slow structural changes at the whole-organism level. 8
What sequences of the genome do in fact reside the causal differences responsible for morphological diversity, and how exactly do they function? A large part of the answer lies in the gene control circuitry encoded in the DNA, its structure, and its functional organization. The regulatory interactions mandated by this circuitry determine whether each gene is expressed in every cell, throughout developmental space and time. The control circuitry encoded in the DNA is comprised of cis-regulatory elements, i.e., the regions in the vicinity of each gene which contain the specific sequence motifs at which those regulatory proteins which affect its expression bind; plus the set of genes which encode these specific regulatory proteins (i.e., transcription factors).
In the same sense, as on top is a master plan, a general layout of an industrial complex of various interlinked factory buildings, and below are the blueprints to make the individual factories, compartments, assembly lines, machines, robots, machine elements, basic building blocks, material specification, in biology there is as well a master plan, which outlines the entire structure and body architecture of an organism. That master plan is stored in the genome, in a section, called homeobox. 2
Homeobox genes are a large family of similar genes that direct the formation of many body structures during early embryonic development. A homeobox is a DNA sequence found within genes that are involved in the regulation of patterns of anatomical development morphogenesis in animals, fungi, and plants. In humans, the homeobox gene family contains an estimated 235 functional genes and 65 pseudogenes, which are structurally similar genes that do not provide instructions for making proteins. Homeobox genes are present on every human chromosome, and they often appear in clusters. Many classes and subfamilies of homeobox genes have been described, although these groupings are used inconsistently. 1
Homeoboxes have been found in fungi, plants and animals. In each "kingdom" homeobox genes occupy a key position in the genetic control of either cell differentiation, morphogenesis and or body plan specification. 4 The degree of sequence conservation of the homeodomain is extremely high indicating strong functional constraints leading to a high pressure to retain the homeobox sequences constant.
That raises the question of how these sequences emerged in the first place.
Certain clusters of homeotic genes, such as the Antp cluster in Drosophila and its homologous cluster, called HoxA-D in vertebrates, are responsible for anterior-posterior specification of body segments as well as being functionally tied to limb generation in mammals.
Homeobox genes encode transcription factors that bind DNA in a sequence-specific fashion through the homeodomain motif and control the expression of their target genes in a huge range of developmental processes. It is difficult to find a developmental gene network in animals that does not include a homeobox gene. These genes are taxonomically widespread, being found in animals, plants, fungi, and protists. Another notable feature of animal homeobox genes is that a number of them exist in clusters that are widespread across the animal kingdom. These include clusters of genes from the
- ANTP-class (e.g., Hox, ParaHox, NK, Mega-homeobox, and SuperHox clusters), the
- PRD-class (the HRO cluster and its extension), the
- TALE-class (Irx cluster), and
- the SINE-class (SIX cluster), as well as an intriguing
- “pharyngeal”gene cluster composed of different classes of homeobox gene as well as other gene families
A homeobox is a DNA sequence, around 180 base pairs long, found within genes that are involved in the regulation of patterns of anatomical development (morphogenesis) in animals, fungi and plants. 1 The Hox family of clustered homeobox genes plays a fundamental role in the morphogenesis of the vertebrate embryo, providing cells with regional information along the main body axis. Homeobox genes are master developmental control genes that act at the top of genetic hierarchies regulating aspects of morphogenesis and cell differentiation in animals. The homeobox was shown to occur in all metazoa ranging from sponges to vertebrates and also in plants and fungi, and has thus been conserved ( not changed ) throughout the three kingdoms of multicellular organisms
There is uncertainty in our understanding of homeobox gene cluster evolution at present. This relates to our still rudimentary understanding of the dynamics of genome rearrangements and evolution over the evolutionary timescales being considered when we compare lineages from across the animal kingdom. 3
Transcriptional Regulation by Trithorax-Group Proteins
Tritorax proteins induce an open configuration of DNA-chromatin (euchromatin), activating the HOX network. 5
All cells in an organism must be able to “remember” what type of cell they are meant to be. This process, referred to as “cellular memory” or “transcriptional memory,” requires two basic classes of mechanisms. The first class functions to maintain an “off” state for genes that, if turned on, would specify an inappropriate cell type. The Polycomb-group (PcG) proteins have as their primary function a repressive role in cellular memory. The second class of mechanisms is composed of those that are required to maintain key genes in an “on” state. Any cell type requires the expression of master regulatory proteins that direct the specific functions required for that cell type. The genes that encode these master regulatory proteins must be maintained in an “on” state throughout the lifetime of an organism to maintain the proper cell types within that organism.
The proteins that are involved in maintaining the “on” state are called trithorax-group (trxG) proteins in honor of the trithorax gene, the founding member of this group of regulatory proteins. A large group of proteins with diverse functions make up the trxG. The roles these proteins play in the epigenetic mechanisms that maintain the “on” state appear more complex at this juncture than the roles for PcG proteins in repression. The first complexity is that a very large number of proteins and mechanisms are needed to actively transcribe RNA from any gene. Thus, in contrast to repression, which might be accomplished by comparatively simple mechanisms that block access of all proteins, activation of a gene requires numerous steps, any of which might play a role in maintaining an “on” state. Thus, there are numerous possible stages in which a trxG protein might work.
Numerous developmental decisions—including the determination of cell fates—are made in response to transient positional information in the early embryo. These decisions are dependent on changes in gene expression. This allows cells with identical genetic blueprints to acquire unique identities and follow distinct pathways of differentiation. The changes in gene expression underlying the determination of cell fates are heritable; a cell’s fate rarely changes once it is determined, even after numerous cell divisions and lengthy periods of developmental time. Understanding the molecular mechanisms underlying the maintenance of the determined state has long been a goal of developmental and molecular biologists. 6
Chromatin state often plays a critical role in gene regulation, but alterations in chromatin state may not necessarily lead to heritable changes. 3 Much remains unknown about the potential mechanisms for heritability of histone modifications, but evidence indicates that differences in histone modifications between two cells will not necessarily be transmitted through mitosis or meiosis.
Epigenetic gene regulation involves changes in gene expression that can be passed from cell to cell and are reversible but does not involve a change in the base sequence of DNA.
Some epigenetic changes are passed from parent to offspring. In multicellular species that reproduce via gametes (sperm and egg cells), the passing of an epigenetic change from parent to offspring is called epigenetic inheritance. Genomic imprinting is an epigenetic change that is passed from parent to offspring. However, not all epigenetic changes fall into this category. For example, an individual may be exposed to an environmental agent that causes an epigenetic change in a lung cell that is subsequently transmitted from cell to cell and promotes lung cancer. Such a change would not be transmitted to the individual’s offspring. In this section, we will begin by examining the molecular changes that cause epigenetic gene regulation. We will then consider how such changes may be programmed into an organism’s development or caused by environmental agents.
a A cell capable of contributing to the establishment of one or more cell populations but is not a stem cell.
b Segmentation is a difficult process to satisfactorily define. Many taxa (for instance the molluscs) have some form of serial repetition in their units, but are not conventionally thought of as segmented. Segmented animals are those considered to have organs that were repeated, or to have a body composed of self-similar units, but usually it is the parts of an organism that are referred to as being segmented. 12
Somites (outdated: primitive segments) are divisions of the body of an animal or embryo.
Somites are bilaterally paired blocks of paraxial mesoderm that form along the head-to-tail axis of the developing embryo in segmented animals. In vertebrates, somites subdivide into the sclerotomes, myotomes and dermatomes that give rise to the vertebrae of the vertebral column, rib cage, and part of the occipital bone; skeletal muscle, cartilage, tendons, and skin (of the back)
4. HOX Gene Expression Spyros Papageorgiou, Ph.D. page 18
16. Behe, edge of evolution, page 117