Chapter SummaryA striking feature of embryonic development is the generation of cellular diversity which makes up the adult animal. This diversity is generated by the production of nonequivalent sibling cells from a precursor cell that is originally nonpolarized; sibling cells arising from a cell division may also be equivalent at birth and attain distinct identities later on when they come to reside in different environments. Cells with distinct identities may in turn communicate with each other by expressing and utilizing signaling molecules.
Yeast cells, which are the simplest eukaryotes, undergo asymmetric cell division to give rise to cells with distinct fates which are brought about after the cell division has already occured. Briefly a mother cell buds of a daughter cell with the same mating type (a or a ). After cell division has been completed, the mother cell switches its mating type; this process is now known to be regulated by products encoded by the genes, Ash1p and Ho. Mating type conversion helps ensure that the cells of the opposite mating types are in close proximity to one another, thereby enabling mating, which occurs only between cells of opposite mating types.
Among metazoans, the significance of asymmetric divisions during development has been demonstrated in the nematode C. elegans. The C. elegans embryo cleaves asymmetrically into two cells- anterior-AB and posterior-P1. The AB cell gives rise to an anterior daughter ABa and posterior daughter Abp. The P1 cell gives rise to P2 and EMS cells, of which the EMS cells divides into the anterior MS cell and the posterior E cell. The specification of the MS and the E cells is dependent on signals transduced from the P2 cell via the Wnt-Frizzled signal transduction pathway. Furthermore, the P2 cell also signals to the Abp cell via the Notch pathway; this signaling event is essential for proper fate specification of Abp (fig. 15.4). Asymmetric cell divisions also play a crucial role in the development of the insect nervous system. This has been particularly well studied in Drosophila melanogaster.
Neuroblasts which delaminate from the ventral neuroectoderm produce a molecule called Numb. Subsequent division of the neuroblasts partitions the Numb protein into the basal cell which becomes the Ganglion Mother Cell (GMC). The apical daughter cell does not inherit any Numb and attains a neuroblasts identity. A similar strategy is employed in the development of sensory bristles, wherein the Sensory Organ Precursor (SOP) cell divides to give rise to an anterior IIa cell and a posterior IIb cell. Cell IIa divides into a sheath cell and a neuron while cell IIb divides into a hair cell and a socket cell. Thus this mode of generating cellular diversity employs inheritance of intracellular determinants. [fig 15.5]
Segregation of cellular fates may also involve inhibitory signals; this phenomenon, known as lateral inhibition, functions to maintain the separate identities established by asymmetric cell division. Lateral inhibition is very often known to involve the Notch signal transduction pathway and is known to play a role in events as diverse as the development of the insect nervous system, genitalia in the nematode, and C. elegans and also the differentiation of T-cells in the mammalian immune system.
Drosophila is a segmented animal; segmentation and organization of the embryo along the anteroposterior and dorsoventral axes depends on gradients of molecules such as Bicoid, Nanos, and Dorsal in the early embryo. The genes involved in the organization of the embryo into segments are divided into three main categories: gap genes, pair-rule genes, and segment polarity genes. These groups of genes are expressed and function in a sequential manner. Gap genes (nanos, hunchback, tailless, huckebien, giant, kruppel, and knirps) interact with each other and define broad domains in the embryo. The establishment of these domains may involve both positive and negative regulation of one gap gene by another. These domains set up conditions for regulating the pair-rule genes. All eight-pair rule genes encode transcription factors; three of them (even-skipped, hairy, and runt) are called the primary-pair rule genes and are expressed early on and the other five (ftz, opa, odd, slp, and prd), which are expressed later are called secondary-pair rule genes. The primary and secondary pair-rule genes are expressed in seven stripes. Their domains of expression overlap slightly with each other, thereby creating a complex pattern of expression. The seven broad stripes created by each of the pair-rule genes regulate the segment polarity genes. The segment polarity genes products function to subdivide the expression domain of each of the seven stripes into two subdomains. Thus 14 subdomains are formed which become the 14 parasegments of the first-instar larva. The anterior and posterior portions of a parasegment are morphologically distinct, in that the anteroventral portion of a parasegment possesses small hairlike projections called Denticles which are absent in the posterioventral portion. [fig 15.9]
The resolution of eve expression into seven stripes is dependent on the modular binding sites present on its regulatory region. Sites regulating expression of stripes 2, 3 and 7 are located upstream of the eve coding region, whereas modules regulating expression of stripes 1, 4, 5, and 6 are located downstream. Modules regulating the expression of stripes 2, 3, and 7 interact with proteins encoded by the gap genes such as bcd, hb, Kr, and gt. Activating and suppressing interactions compete with one another to determine whether eve will be turned on or not. Together with Hairy and Runt, the Eve protein generated by these earlier activated stripes activates a later enhancer sequence, which helps activate transcription of the other four stripes. [fig 15.14]
Homeotic selector genes regulate segment identity by regulating the expression of a select set of target genes in a segment specific manner. Homeotic genes have been extensively studied in Drosophila melanogaster due to ease of genetic manipulations used to generate mutants. The main homeotic genes in Drosophila are in two complexes-the bithorax complec (BX-C) and the Antennepedia complex (ANT-C). The BX-C is made up of three genes: ultrbithorax (ubx), abdominal A (abdA), and abdominal B (abdB). The ANT-C is made up of five genes: labial (lab), proboscipedia (pb), deformed (dfd), sex-combs-reduced (scr) and antennepedia (antp). ANT-C genes control anterior segment identities whereas the BX-C genes control posterior segment identities. The functional domains of homeotic genes are complex; all homeotic genes encode transcription factors, and each transcription factor contains a domain called the homeodomain, which binds DNA and regulates transcription. The linear order of arrangement of the homeotic genes in the DNA is identical to the linear order of their spatial expression in the embryo.
A specific character of homeotic genes is that when the function of one gene is eliminated, the segment in which it is ordinarily expressed adopts an identity like that of the segment anterior to it. For example when ubx is deleted, the third thoracic segment and first abdominal segments are not specified; both attain a T2 identity. This is because of posterior dominance of homeotic selector genes; posteriorly expressed genes repress genes which are expressed more anteriorly. Thus homeotic genes interact among themselves to establish domains of expression along the anterior-posterior axis, and they ultimately govern a hierarchy of other genes that accomplish specific local differentiation programs. This is achieved by regulating the expression of target genes such as those coding for specific forms of tubulin, adhesion molecules, and many other genes.
Intercellular signaling, in addition to playing a role in cell fate specification, also plays a role in organogenesis and differentiation of particular compartments in an organ. In this context, the Drosophila wing is one of the best studied and understood systems. The Drosophila wing, like most other appendages of insects, develops from an imaginal disc. Development of the adult from the imaginal disc entails complex signaling interactions that divide the disc into distinct anterior, posterior, dorsal, and ventral compartments.
One of the genes to play an early role in patterning the anterior and posterior compartments is engrailed, which also plays a role in establishing parasegmental boundaries in the early embryo. Posterior compartment cells of the wing express engrailed while the anterior compartment cells do not. Thus the border of the engrailed expression domain marks the A/P boundary. The posterior compartment cells, which express engrailed also express Hedgehog (Hh), a signaling molecule. Hh signals to the cells in the anterior compartment through its membrane bound receptor Patched (Ptc) and a partner molecule called Smoothened (Smo). The Hh signaling pathway is thus activated in a narrow band of cells along the A/P boundary. These cells activate the expression of Dpp, which is a diffusible long-range signaling molecule. Dpp diffuses toward both the anterior and posterior cells and thus establishes a gradient and activates downstream target genes in a concentration dependent manner. Genes requiring low concentrations of Dpp are thus activated away from the A/P boundary while those requiring higher Dpp concentrations are activated at or closer to the A/P boundary. [fig 15.25]
Patterning of the dorsal and ventral compartments of the wing also involves complex signaling pathways. The cells in the dorsal compartment express the homeobox gene apterous (apt) and fringe (fng) while the ventral compartment cells do not; hence a sharp border of apt expression marks the D/V boundary. Apterous protein induces the expression of serrate (ser) in the dorsal cells. Serrate is a ligand for the ubiquitously present Notch receptor; however, Fringe, which is expressed in the dorsal cells, reduces the sensitivity of the Notch receptor to Serrate. The Notch receptor nonetheless is still responsive to its other ligand Delta which is expressed by the ventral compartment cells. This set of interactions leads to a band of Notch activation along the D/V boundary resulting in a band of wingless expression along the D/V border. Wingless signals through its receptor and activates the expression of the downstream target genes distalless and vestigial.
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