The Interactive Fly
Evolutionarily conserved developmental pathways
Most Drosophila pair rule genes are initially transcribed in alternating segments, although one of them, odd-paired, is expressed ubiquitously, and four others (odd skipped, paired, runt and sloppy paired ) exhibit a late 14 stripped pattern. Many are involved in neural patterning. This is not surprising as each neuroblast exhibits a uniquely defined fate due in large part to the action of pair rule genes. even-skipped carries out a late function in heart development and odd-paired is involved in mesodermal patterning. It is not surprising that pair rule genes are involved in mesodermal patterning, since pair rule genes are expressed prior to gastrulation and their domain of expression includes the presumptive mesoderm. sloppy paired performs an early function in head patterning.
Six pair rule proteins, Even-skipped, Hairy, Odd-paired, Paired, Runt and Tenascin major, have well defined mammalian homologs. These genes play distinct roles in ectodermal, mesodermal and neural patterning. For a description of Tenascin major's conserved developmental role, see Extracellular matrix: functional conservation of extracellular modular proteins and cell surface receptors. The other conserved pair rule genes play roles in ectodermal, neural and mesodermal patterning.
Evx-1, the mammalian homolog of Drosophila even-skipped, is involved in patterning of ectoderm and mesoderm and is first expressed prior to gastrulation. Murine Evx-1 is first translated shortly before the onset of gastrulation in a region of ectoderm containing cells that will shortly be found in the primitive streak. This localized expression of Evx-1 provides the first molecular evidence for regional differences in the mouse embryonic ectoderm before gastrulation. Throughout gastrulation, Evx-1 expression is limited to cells near and within the streak; this expression is graded, with a posterior-to-anterior decrease in the level of RNA. Evx-1 is involved later in mouse limb bud patterning. Evx-1 RNA is first detected in distal limb mesenchyme shortly after the formation of the apical ectodermal ridge. Evx-1 RNA is localized primarily to the posterior distal mesenchyme (a mesodermal tissue), in the region immediately underlying that portion of the ridge in which the Fgf-4 gene is expressed. The ridge is required for both the induction and maintenance of Evx-1 expression in the distal mesenchyme (Dush, 1992 and Niswander, 1993).
Hairy's mammalian homologs function as repressors in neural patterning. Because Hairy is structurally related to Enhancer of split proteins and because the function of Hairy is to oppose neurogenesis, the mammalian Hairy homolog is called, confusingly, Hairy and enhancer of split homolog (HES-1). Mammalian HES-1 encodes a helix-loop-helix (HLH) factor that is thought to act as a negative regulator of neurogenesis. Knockout mice homozygous for HES-1 mutation exhibit severe neurulation defects and die during gestation or just after birth. In the developing brain of HES-1-null embryos, expression of the neural differentiation factor Mash-1 and other neural HLH factors are up-regulated and postmitotic neurons appear prematurely. These results suggest that HES-1 normally controls the proper timing of neurogenesis and regulates neural tube morphogenesis. During early development of the central nervous system, HES-3, another Hairy homolog is expressed specifically in the region of the midbrain/hindbrain boundary, and in rhombomeres 2, 4, 6 and 7. This pattern occurs at approximately the same time that Krox20 expression appears in r3 and r5 and precedes the morphological appearance of rhombomeres. The segmental pattern of HES-3 suggests that it may have a conserved role as a segmentation gene. Later in development, HES-3 is co-expressed with other neurogenic gene homologs in the developing central nervous system and epithelial cells undergoing mesenchyme induction (Ishibashi, 1995 and Lobe, 1997).
Odd-paired homologs are called Zic proteins, due to the presence of a conserved zinc finger DNA binding domain. The mouse Zic gene, which encodes a zinc finger protein, is expressed in a highly restricted manner in the developing or matured central nervous system. The expression of the three Zic genes is first detected at gastrulation in a spatially restricted pattern. Zic2 is detected only in the presumptive headfold region, whereas Zic3 is expressed mainly in the primitive streak. The expression of both genes continues during neural tube formation. At the late primitive streak stage, Zic1 expression in the neuroectoderm is detected in the presumptive dorsal region. All three Zic genes are expressed only in dorsal axial structures. During organogenesis, the three genes are expressed in specific regions of several developing organs, including dorsal areas of the brain, spinal cord, paraxial mesenchyme, and epidermis, and the marginal zone of the neural retinal and distal regions of the developing limb. In all cases significant differences are observed in the spatial patterns of the three genes. Zic proteins are expressed in a restricted manner in the cerebellum at the adult stage. The temporal profile of the mRNA expression in the developing cerebellum differs among in the Zic genes, suggesting the specialization of each protein in cerebellar patterning (Aruga, 1996, Nagai, 1997).
Mammalian homologs of Paired are involved in both neural and mesodermal patterning. Specification of the myogenic lineage begins prior to gastrulation and culminates in the emergence of determined myogenic precursor cells from the somites. The Pax-3 gene is expressed in all the cells of the caudal segmental plate, the early mesoderm compartment that contains the precursors of skeletal muscle. As somites form from the segmental plate and mature, Pax-3 expression is progressively modulated. Beginning at the time of segmentation, Pax-3 becomes repressed in the ventral half of the somite, leaving Pax-3 expression only in the dermomyotome. Subsequently, differential modulation of Pax-3 expression levels delineates the medial and lateral halves of the dermomyotome, which contain (respectively) precursors of axial (back) muscle and limb muscle. The limb muscles of vertebrates are derived from precursor cells that migrate from the lateral edge of the dermomyotome into the limb bud. Pax-3 is expressed in limb cells that are precursors for limb muscles. In splotch (Pax-3-) embryos, the limb muscles fail to develop and cells expressing Pax-3 are no longer found in the limb. It has been concluded that Pax-3 regulates the migration of limb muscle precursors into the limb. Pax-3 is specifically expressed in the dorsal and posterior neural tube. Pax-3 expression is initiated by signals that posteriorize the neuraxis, and then secondarily restrict dorsal neural tube development in response to dorsal-ventral patterning signals. In chick and Xenopus gastrulae the onset of Pax-3 expression occurs in regions fated to become posterior CNS. Hensen's node and posterior non-axial mesoderm (which underlies the neural plate) induce Pax-3 expression when combined with presumptive anterior neural plate explants (Bang, 1997, Blumberg, 1997, Williams 1994).
Runt homologs are involved in bone development. This is obviously not a conservation of developmental function, since flies do not have bones. Mammalian Runt homologs known by three names: either osteoblast-specific transcription factor (OSF), core binding factor (CBF) or polyoma enhancer-binding protein (PEBP). Cbfa1/Osf2 is expressed from day 10.5 of fetal development in developing limbs. Cbfa1 is first detected in the region surrounding cartilaginous condensation and in limb tendons from 13.5 days after fertilization. Mice with a homozygous mutation in Cbfa1 die just after birth without breathing. Examination of their skeletal systems shows a complete lack of ossification. Although immature osteoblasts and a few immature osteoclasts appeared at the perichondrial region, neither vascular nor mesenchymal cell invasion is observed in the cartilage. This suggests that both intramembranous and endochondral ossification are completely blocked, owing to the maturational arrest of osteoblasts in the mutant mice, and demonstrates that Cbfa1 plays an essential role in osteogenesis (Komori, 1997).
REFERENCES
Aruga, J., et al. (1996). Identification and characterization of Zic4, a new member of the mouse Zic gene family. Gene 172: 291-294 Medline abstract
Bang, A. G., et al. (1997). Expression of Pax-3 is initiated in the early neural plate by posteriorizing signals produced by the organizer and by posterior non-axial mesoderm. Development 124: 2075-2085. Medline abstract: 97313249
Blumberg, B., et al. (1997). An essential role for retinoid signaling in anteroposterior neural patterning. Development 124: 373-379
Dush M. K. and Martin, G. R. (1992). Analysis of mouse Evx genes: Evx-1 displays graded expression in the primitive streak. Dev Biol 151: 273-87
Ishibashi, M., et al. (1995). Targeted disruption of mammalian hairy and Enhancer of split homolog-1 (HES-1) leads to up-regulation of neural helix-loop-helix factors, premature neurogenesis, and severe neural tube defects. Genes Dev. 9: 3136-3148
Jiménez, G., Pinchin, S. M. and Ish-Horowicz, D. (1996). In vivo interactions of the Drosophila Hairy and Runt transcriptional repressors with target promoters. EMBO J. 7088-7098
Komori, T., et al. (1997). Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 89 (5): 755-764. Medline abstract: 97325751
Lobe, C. G. (1997). Expression of the helix-loop-helix factor, Hes3, during embryo development suggests a role in early midbrain-hindbrain patterning. Mech. Dev. 62 (2): 227-237. Medline abstract: 97296449
Nagai, T., et al. (1997). The expression of the mouse Zic1, Zic2 and Zic3 genes suggests an essential role for Zic genes in body pattern formation. Dev. Biol. 182: 299-313
Niswander, L. and Martin, G. R. (1993). FGF-4 regulates expression of Evx-1 in the developing mouse limb. Development 119: 287-94
Williams, B. A. and Ordahl, C. P. (1994). Pax-3 expression in segmental mesoderm marks early stages in myogenic cell specification. Development 120: 785-796. Medline abstract: 95324366
date revised: 15 July 97
Developmental Pathways conserved in Evolution
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