Compartments can be simply defined as separate, different, adjacent cell populations, which upon juxtaposition, create a lineage boundary.This boundary prevents cell movement from cells from different lineages across this barrier, restricting them to their compartment. Subdivisions are established by morphogen gradients and maintained by local cell-cell interactions, providing functional units with domains of different regulatory genes, which give rise to distinct fates. Compartment boundaries are found across species. In the hindbrain of vertebrate embryos, rhobomeres are compartments of common lineage outlined by expression of Hox genes. In invertebrates, the wing imaginal disc of Drosophila provides an excellent model for the study of compartments. Although other tissues, such as the abdomen, and even other imaginal discs are compartmentalized, much of our understanding of key concepts and molecular mechanisms involved in compartment boundaries has been derived from experimentation in the wing disc of the fruit fly.
By separating different cell populations, the fate of these compartments are highly organized and regulated.In addition, this separation creates a region of specialized cells close to the boundary, which serves as a signaling center for the patterning, polarizing and proliferation of the entire disc. Compartment boundaries establish these organizing centers by providing the source of morphogens that are responsible for the positional information required for development and regeneration. The inability of cell competition to occur across the boundary, indicates that each compartment serves as an autonomous unit of growth. Differences in growth rates and patterns in each compartment, maintain the two lineages separated and each control the precise size of the imaginal discs.
These two cell populations are kept separate by a mechanism of cell segregation linked to the heritable expression of a selector gene.A selector gene is one that is expressed in one group of cells but not the other, giving the founder cells and their descendants different instructions. Eventually these selector genes become fixed in either an expressed or unexpressed state and are stably inherited to the descendants, specifying the identity of the compartment and preventing these genetically different cell populations from intermixing. Therefore, these selector genes are key for the formation and maintenance of lineage compartments.
The difference in selector gene activity not only establishes two compartments, but also leads to the formation of a boundary between these two that serves as a source of morphogen gradients. In the central dogma of compartments, first, morphogen gradients position founder compartment cells.Then, active/inactive selector genes give a unique genetic identity to cells within a compartment, instructing their fate and their interactions with the neighboring compartment. Finally, border cells, established by short-range signaling from one compartment to its neighboring compartment emit long-range signals that spread to both compartments to regulate the growth and pattering of the entire tissue.
In 1970, by means of clonal analysis, the Anterior-Posterior boundary was identified.The founder cells, found at the border between parasegments 4 and 5 of embryo, are already determined at the early blastoderm stage and defined into the two populations they will generate by stripes of the engrailed gene. The selector gene, engrailed (en), is a key determinant in boundary formation between the anterior and posterior compartments. As the wing imaginal disc expands, posterior, but not anterior cells will express engrailed and maintain this expression state as they expand and form the disc. Engrailed mutant clones of posterior origin will gain anterior affinity and move towards the anterior compartment and intermix with those cells. Within the posterior compartment these clones will sort out and form an ectopicborder where they meet other posterior cells. Similarly, a clone of anterior cells expressing engrailed will gain posterior identity and create an ectopic boundary where the clone meets other anterior cells in this compartment. In addition, to its cell autonomous role in specifying posterior compartment identity, engrailed also has a non-cell autonomous function in the general growth and patterning of the wing disc, through the activation of signaling pathways such as Hedgehog (Hh) and Decapentaplegic (Dpp). The presence of engrailed in the posterior cells leads to the secretion of the short-range inducer Hh which can cross over to the anterior compartment to activate the long-range morphogen, Dpp. Cells in the posterior compartment produce Hh, but only anterior cells can transduce the signal. Optomotor-blind (omb) is involved in the transcriptional response of Dpp, which is only required in the anterior cells to interpret Hh signaling for boundary formation and maintenance. In addition, Cubitus interruptus (Ci), the signal transducer of the Hh signal, is expressed throughout the anterior compartment, particularly in anterior border cells. In posterior cells engrailed prevents the expression of Ci, such it is only expressed in anterior cells and hence only these cells can respond to Hh signaling by up-regulating the expression of dpp. Loss of engrailed function in posterior cells, results in anterior transformation, where Hh expression is decreased and dpp, ci and patched (ptc) is increased, resulting in the formation of a new A/P boundary, suggesting that en positively regulates hh, while negatively regulating ci, ptc and dpp.
To explain how anterior and posterior cells are kept separated, the differential adhesion hypothesis proposes that these two cell populations express different adhesion molecules, producing different affinities for each other that minimize their contact.The selector affinity model proposes that difference in cell affinity between compartments is a result of differential selector gene expression. The presence or absence of selector genes in a given compartment produces compartment-specific adhesion or recognition molecules that are different from those in its counterpart. For example, engrailed expressed in the posterior, but not the anterior, cells provides the differential affinity that keeps these compartments separately. It is also possible that this difference in cell adhesion/affinity is not directly due to en expression, but rather to the ability to receive Hh signaling. Anterior cells, capable of Hh transduction, will express given adhesive molecules that would differ from those present in posterior cells, creating differential affinity that would prevent them from intermixing. This signaling-affinity model is supported by experiments that demonstrate the importance of Hh signaling. Clones mutant for the Smoothened (smo), the gene responsible for transducing Hh signaling, retain anterior-like features, but move into the posterior compartment without any changes in the expression engrailed or invected. This demonstrates that Hh signaling, rather than the absence of en, is what gives cells their compartmental identity. Nonetheless, this signaling-affinity model is incomplete: smo mutant clones of anterior origin that migrate into the posterior compartment, do not completely associate with these cells, but rather form a smooth boundary with these posterior cells. If signaling-affinity were the only factor determining compartment identity, then these clones, which are no longer receiving Hh signaling, would have the same affinity as the other posterior cells in that compartment and be able to intermix with them. These experiments indicate that although Hh signaling could be having an effect in adhesive properties, this effect is limited to the border cells rather than throughout both compartments. It is also possible that both compartments produce the same cell adhesion molecules, but a difference in its abundance or activity could result in sorting between the two compartments. In vitro, transfected cells with high levels of a given adhesion molecule will segregate from cells that expressing lower levels of this same molecule. Finally, differences in cell bond tension could also play a role in the establishment of the boundary and the separation of the two different cell populations. Experimental data has shown that Myosin-II is up-regulated along both the dorsal-ventral and anterior-posterior boundaries in the imaginal wing disc. The D/V boundary is characterized by the presence of filamentous actin and mutations in Myosin-II heavy chain impairs D/V compartmentalization. Similarly, both F-actin and Myosin-II are increased along the A/P boundary, accompanied by a decrease of Bazooka, which was also observed in the D/V border. The Rho-kinase inhibitor Y-27632, of which Myosin-II is the main target, significantly reduces cell bond tension, suggesting that Myosin-II could be the main effector of this process. In support of the signaling-affinity model, creating an artificial interface between cells with active vs. inactive Hh signaling induces a junctional behavior that aligns the cell bonds of where these opposing cell types meet. Moreover, a 2.5-fold increase in mechanical tension is observed along the A/P boundary, compared to the rest of the tissue. Simulations using a vertex model demonstrate that this increase in cell bond tension is enough to maintain proliferating cell populations in separate compartment boundaries. Parameters used to measure cell bond tension are based cell-cell adhesion and cortical tension input. It has also been suggested that boundary formation is not a result of differential mechanical tension between the two cell populations, but could be a result of the mechanical properties of the boundary itself. The level the adhesion molecule, E-cadherin, was unaltered and the biophysical properties of cells between the two compartments were the same. Changes in cell properties, such as an enlarged apical cross-section area, are only observed in anterior and posterior border cells. Along the boundary, orientation of cell divisions was random and there is no evidence that increased cell death or zones of non-proliferating cells are important for maintaining the A/P or D/V boundary.
Despite many attempts to identify the adhesion molecules important for the establishment and maintenance of compartment boundaries, none have been identified.Continuation of our understanding of this process will benefit from further experimental data on cell bonds and cortical tension, as well as screens to identify molecules regulating differential cell affinity.
Morphogenesis is the biological process that causes a cell, tissue or organism to develop its shape. It is one of three fundamental aspects of developmental biology along with the control of tissue growth and patterning of cellular differentiation.
Drosophila embryogenesis, the process by which Drosophila embryos form, is a favorite model system for genetics and developmental biology. The study of its embryogenesis unlocked the century-long puzzle of how development was controlled, creating the field of evolutionary developmental biology. The small size, short generation time, and large brood size make it ideal for genetic studies. Transparent embryos facilitate developmental studies. Drosophila melanogaster was introduced into the field of genetic experiments by Thomas Hunt Morgan in 1909.
Segmentation in biology is the division of some animal and plant body plans into a series of repetitive segments. This article focuses on the segmentation of animal body plans, specifically using the examples of the taxa Arthropoda, Chordata, and Annelida. These three groups form segments by using a "growth zone" to direct and define the segments. While all three have a generally segmented body plan and use a growth zone, they use different mechanisms for generating this patterning. Even within these groups, different organisms have different mechanisms for segmenting the body. Segmentation of the body plan is important for allowing free movement and development of certain body parts. It also allows for regeneration in specific individuals.
In evolutionary developmental biology, homeosis is the transformation of one organ into another, arising from mutation in or misexpression of certain developmentally critical genes, specifically homeotic genes. In animals, these developmental genes specifically control the development of organs on their anteroposterior axis. In plants, however, the developmental genes affected by homeosis may control anything from the development of a stamen or petals to the development of chlorophyll. Homeosis may be caused by mutations in Hox genes, found in animals, or others such as the MADS-box family in plants. Homeosis is a characteristic that has helped insects become as successful and diverse as they are.
A morphogen is a substance whose non-uniform distribution governs the pattern of tissue development in the process of morphogenesis or pattern formation, one of the core processes of developmental biology, establishing positions of the various specialized cell types within a tissue. More specifically, a morphogen is a signaling molecule that acts directly on cells to produce specific cellular responses depending on its local concentration.
The Hedgehog signaling pathway is a signaling pathway that transmits information to embryonic cells required for proper cell differentiation. Different parts of the embryo have different concentrations of hedgehog signaling proteins. The pathway also has roles in the adult. Diseases associated with the malfunction of this pathway include cancer.
Ultrabithorax (Ubx) is a homeobox gene found in insects, and is used in the regulation of patterning in morphogenesis. There are many possible products of this gene, which function as transcription factors. Ubx is used in the specification of serially homologous structures, and is used at many levels of developmental hierarchies. In Drosophila melanogaster it is expressed in the third thoracic (T3) and first abdominal (A1) segments and represses wing formation. The Ubx gene regulates the decisions regarding the number of wings and legs the adult flies will have. The developmental role of the Ubx gene is determined by the splicing of its product, which takes place after translation of the gene. The specific splice factors of a particular cell allow the specific regulation of the developmental fate of that cell, by making different splice variants of transcription factors. In D. melanogaster, at least six different isoforms of Ubx exist.
The apical ectodermal ridge (AER) is a structure that forms from the ectodermal cells at the distal end of each limb bud and acts as a major signaling center to ensure proper development of a limb. After the limb bud induces AER formation, the AER and limb mesenchyme—including the zone of polarizing activity (ZPA)—continue to communicate with each other to direct further limb development.
Decapentaplegic (Dpp) is a key morphogen involved in the development of the fruit fly Drosophila melanogaster and is the first validated secreted morphogen. It is known to be necessary for the correct patterning and development of the early Drosophila embryo and the fifteen imaginal discs, which are tissues that will become limbs and other organs and structures in the adult fly. It has also been suggested that Dpp plays a role in regulating the growth and size of tissues. Flies with mutations in decapentaplegic fail to form these structures correctly, hence the name. Dpp is the Drosophila homolog of the vertebrate bone morphogenetic proteins (BMPs), which are members of the TGF-β superfamily, a class of proteins that are often associated with their own specific signaling pathway. Studies of Dpp in Drosophila have led to greater understanding of the function and importance of their homologs in vertebrates like humans.
In the field of developmental biology, regional differentiation is the process by which different areas are identified in the development of the early embryo. The process by which the cells become specified differs between organisms.
Peter Anthony Lawrence is a British developmental biologist at the Laboratory of Molecular Biology and the Zoology Department of the University of Cambridge. He was a staff scientist of the Medical Research Council from 1969 to 2006.
An eyespot is an eye-like marking. They are found in butterflies, reptiles, cats, birds and fish.
The French flag model is a conceptual definition of a morphogen, described by Lewis Wolpert in the 1960s. A morphogen is defined as a signaling molecule that acts directly on cells to produce specific cellular responses dependent on morphogen concentration. During early development, morphogen gradients generate different cell types in distinct spatial order. French flag patterning is often found in combination with others: vertebrate limb development is one of the many phenotypes exhibiting Turing overlapped with a complementary pattern.
Homeobox protein engrailed-1 is a protein that in humans is encoded by the EN1 gene.
engrailed is a homeodomain transcription factor involved in many aspects of multicellular development. First known for its role in arthropod embryological development, working in consort with the Hox genes, engrailed has been found to be important in other areas of development. It has been identified in many bilaterians, including the arthropods, vertebrates, echinoderms, molluscs, nematodes, brachiopods, and polychaetes. It acts as a "selector" gene, conferring a specific identity to defined areas of the body, and co-ordinating the expression of downstream genes.
The zone of polarizing activity (ZPA) is an area of mesenchyme that contains signals which instruct the developing limb bud to form along the anterior/posterior axis. Limb bud is undifferentiated mesenchyme enclosed by an ectoderm covering. Eventually, the limb bud develops into bones, tendons, muscles and joints. Limb bud development relies not only on the ZPA, but also many different genes, signals, and a unique region of ectoderm called the apical ectodermal ridge (AER). Research by Saunders and Gasseling in 1948 identified the AER and its subsequent involvement in proximal distal outgrowth. Twenty years later, the same group did transplantation studies in chick limb bud and identified the ZPA. It wasn't until 1993 that Todt and Fallon showed that the AER and ZPA are dependent on each other.
Cytonemes are thin, cellular projections that are specialized for exchange of signaling proteins between cells. Cytonemes emanate from cells that make signaling proteins, extending directly to cells that receive signaling proteins. Cytonemes also extend directly from cells that receive signaling proteins to cells that make them.
A segmentation gene is a generic term for a gene whose function is to specify tissue pattern in each repeated unit of a segmented organism. Animals are constructed of segments; however, Drosophila segments also contain subdivided compartments. There are five gene classes which each contribute to the segmentation and development of the embryonic drosophila. These five gene classes include the coordinate gene, gap gene, pair-rule gene, segment polarity gene, and homeotic gene. In embryonic drosophila, the pair-rule gene defines odd-skipped and even-skipped genes as parasegments, showing 7 stripes in the embryo. In the next gene class, segment polarity gene, individual segments each have their own anterior and posterior pole, resulting in 14 segments. In the fruit fly Drosophila melanogaster, segment polarity genes help to define the anterior and posterior polarities within each embryonic parasegment by regulating the transmission of signals via the Wnt signaling pathway and Hedgehog signaling pathway. Segment polarity genes are expressed in the embryo following expression of the gap genes and pair-rule genes. The most commonly cited examples of these genes are engrailed and gooseberry in Drosophila melanogaster. The segment polarity is the last step in embryonic development and a repeated pattern where each half of each segment is deleted and a mirror-image is duplicated and reversed to replace that half segment; thus, forming a pattern element.
Germ-band extension is a morphological process widely studied in Drosophila melanogaster in which the germ-band, which develops into the segmented trunk of the embryo, approximately doubles in length along the anterior-posterior axis while subsequently narrowing along the dorsal-ventral axis.
Dally is the name of a gene that encodes a HS-modified-protein found in the fruit fly. The protein has to be processed after being codified, and in its mature form it is composed by 626 amino acids, forming a proteoglycan rich in heparin sulfate which is anchored to the cell surface via covalent linkage to glycophosphatidylinositol (GPI), so we can define it as a glypican. For its normal biosynthesis it requires sugarless (sgl), a gene that encodes an enzyme which plays a critical role in the process of modification of dally.