The control of cell fate in the embryonic visual system by atonal, tailless and EGFR signaling.
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We describe here the role of the transcription factors encoding genes tailless (tll), atonal (ato), sine oculis (so), eyeless (ey) and eyes absent (eya), and EGFR signaling in establishing the Drosophila embryonic visual system. The embryonic visual system consists of the optic lobe primordium, which, during later larval life, develops into the prominent optic lobe neuropiles, and the larval photoreceptor (Bolwig's organ). Both structures derive from a neurectodermal placode in the embryonic head. Expression of tll is normally confined to the optic lobe primordium, whereas ato appears in a subset of Bolwig's organ cells that we call Bolwig's organ founders. Phenotypic analysis, using specific markers for Bolwig's organ and the optic lobe, of tll loss- and gain-of-function mutant embryos reveals that tll functions to drive cells to optic lobe as opposed to Bolwig's organ fate. Similar experiments indicate that ato has the opposite effect, namely driving cells to a Bolwig's organ fate. Since we can show that tll and ato do not regulate each other, we propose a model wherein tll expression restricts the ability of cells to respond to signaling arising from ato-expressing Bolwig's organ pioneers. Our data further suggest that the Bolwig's organ founder cells produce Spitz (the Drosophila TGFalpha homolog) signal, which is passed to the neighboring secondary Bolwig's organ cells where it activates the EGFR signaling cascade and maintains the fate of these secondary cells. The regulators of tll expression in the embryonic visual system remain elusive, as we were unable to find evidence for regulation by the 'early eye genes' so, eya and ey, or by EGFR signaling. (+info)
her1, a zebrafish pair-rule like gene, acts downstream of notch signalling to control somite development.
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During vertebrate embryonic development, the paraxial mesoderm becomes subdivided into metameric units known as somites. In the zebrafish embryo, genes encoding homologues of the proteins of the Drosophila Notch signalling pathway are expressed in the presomitic mesoderm and expression is maintained in a segmental pattern during somitogenesis. This expression pattern suggests a role for these genes during somite development. We misexpressed various zebrafish genes of this group by injecting mRNA into early embryos. RNA encoding a constitutively active form of notch1a (notch1a-intra) and a truncated variant of deltaD [deltaD(Pst)], as well as transcripts of deltaC and deltaD, the hairy-E(spl) homologues her1 and her4, and groucho2 were tested for their effects on somite formation, myogenesis and on the pattern of transcription of putative downstream genes. In embryos injected with any of these RNAs, with the exception of groucho2 RNA, the paraxial mesoderm differentiated normally into somitic tissue, but failed to segment correctly. Activation of notch results in ectopic activation of her1 and her4. This misregulation of the expression of her genes might be causally related to the observed mesodermal defects, as her1 and her4 mRNA injections led to effects similar to those seen with notch1a-intra. deltaC and deltaD seem to function after subdivision of the presomitic mesoderm, since the her gene transcription pattern in the presomitic mesoderm remains essentially normal after misexpression of delta genes. Whereas notch signalling alone apparently does not affect myogenesis, zebrafish groucho2 is involved in differentiation of mesodermal derivatives. (+info)
Periodic repression of Notch pathway genes governs the segmentation of Xenopus embryos.
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During the development of the vertebrate embryo, genes encoding components of the Notch signaling pathway are required for subdividing the paraxial mesoderm into repeating segmental structures, called somites. These genes are thought to act in the presomitic mesoderm when cells form prospective somites, called somitomeres, but their exact function remains unknown. To address this issue, we have identified two novel genes, called ESR-4 and ESR-5, which are transcriptionally activated in the somitomeres of Xenopus embryos by the Su(H)-dependent Notch signaling pathway. We show that the expression of these genes divides each somitomere into an anterior and posterior half, and that this pattern of expression is generated by a mechanism that actively represses the expression of the Notch pathway genes when paraxial cells enter a critical region and form a somitomere. Repression of Notch signaling during somitomere formation requires a negative feedback loop and inhibiting the activity of genes in this loop has a profound effect on somitomere size. Finally we present evidence that once somitomeres form, ESR-5 mediates a positive feedback loop, which maintains the expression of Notch pathway genes. We propose a model in which Notch signaling plays a key role in both establishing and maintaining segmental identity during somitomere formation in Xenopus embryos. (+info)
Math1: an essential gene for the generation of inner ear hair cells.
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The mammalian inner ear contains the cochlea and vestibular organs, which are responsible for hearing and balance, respectively. The epithelia of these sensory organs contain hair cells that function as mechanoreceptors to transduce sound and head motion. The molecular mechanisms underlying hair cell development and differentiation are poorly understood. Math1, a mouse homolog of the Drosophila proneural gene atonal, is expressed in inner ear sensory epithelia. Embryonic Math1-null mice failed to generate cochlear and vestibular hair cells. This gene is thus required for the genesis of hair cells. (+info)
Detailed characterization of the human aorta-gonad-mesonephros region reveals morphological polarity resembling a hematopoietic stromal layer.
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The definitive long-term repopulating human hematopoietic stem cell, which seeds the adult blood system, was previously thought to derive from the extra-embryonic yolk sac. However, there is now considerable evidence that in both avian and murine systems, yolk sac hematopoietic cells are largely a transient, embryonic population and the definitive stem cell, in fact, derives from a distinct region within the embryonic mesoderm, the aorta-gonad-mesonephros region. In the human embryo, an analogous region has been found to contain a cluster of cells distinct from, but closely associated with, the ventral endothelium of the dorsal aorta, the appearance of which is restricted both spatially and temporally. We have used antibodies recognising hematopoietic regulatory factors to further characterise this region in the human embryo. These studies indicate that all factors examined, including vascular endothelial growth factor and its receptor FLK-1, Flt-3 ligand and its receptor STK-1, and stem cell leukemia transcription factor, are expressed by both hematopoietic cells in the cluster and endothelial cells. However, there is some discontinuity in cells directly underlying the cluster. Furthermore, we have identified a morphologically distinct region of densely-packed, rounded cells in the mesenchyme directly beneath the ventral wall of the dorsal aorta, and running along its entire length. In the preumbilical AGM region, directly underlying the hematopoietic cluster, but not at more rostral and caudal levels, this region of mesenchyme expresses tenascin-C, an extracellular matrix glycoprotein known to facilitate cell-cell interactions and migration. This region of cells may therefore provide the microenvironmental support for the intraembryonic development of definitive hematopoietic stem cells, a process in which tenascin-C may play a pivotal role. (+info)
Alternative splicing and embryonic expression of the Xenopus mad4 bHLH gene.
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The cell proliferative activity of the Myc family of basic helix-loop-helix/leucine zipper (bHLHZip) transcription factors is dependent upon binding to the ubiquitous Max protein. In the absence of heterodimerization with Max, Myc protein is unable to efficiently bind to DNA and activate transcription. Members of the Mad family of transcription factors are thought to modulate the cell proliferative effects of the c-myc proto-oncogene by binding to Max, directly competing with the Myc protein for both heterodimerization and DNA binding. Consistent with a role in down-regulating cell division, the murine mad genes are expressed in embryonic tissues undergoing differentiation, often during or shortly after the down-regulation of myc gene expression. Here, we report the isolation and characterization of the first Xenopus mad family member, Xmad4. Maternal Xmad4 transcripts are present at high levels in the oocyte and in the cleavage stage embryo, but almost disappear by the neurula stage. Zygotic expression of the Xmad4 gene is initiated in the epidermis of the late neurula stage, and shortly thereafter, Xmad4 is transiently detectable in the cement and hatching glands. At later stages, expression is also observed in the developing pronephros and liver. Unlike the murine mad4 gene, we find that multiple Xmad4 splice variants exist in Xenopus and that these variants are differentially expressed in both the embryo and the adult. Despite the demonstrated antagonistic role of Mad proteins in the regulation of Myc activity, we show that the over-expression of Xmad4 in the cleavage-stage embryo has no detectable phenotypic effect, suggesting that Myc function is dispensable during early embryonic development. (+info)
Target specificities of Drosophila enhancer of split basic helix-loop-helix proteins.
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Seven Enhancer of split genes in Drosophila melanogaster encode basic-helix-loop-helix transcription factors which are components of the Notch signalling pathway. They are expressed in response to Notch activation and mediate some effects of the pathway by regulating the expression of target genes. Here we have determined that the optimal DNA binding site for the Enhancer of split proteins is a palindromic 12-bp sequence, 5'-TGGCACGTG(C/T)(C/T)A-3', which contains an E-box core (CACGTG). This site is recognized by all of the individual Enhancer of split basic helix-loop-helix proteins, consistent with their ability to regulate similar target genes in vivo. We demonstrate that the 3 bp flanking the E-box core are intrinsic to DNA recognition by these proteins and that the Enhancer of split and proneural proteins can compete for binding on specific DNA sequences. Furthermore, the regulation conferred on a reporter gene in Drosophila by three closely related sequences demonstrates that even subtle sequence changes within an E box or flanking bases have dramatic consequences on the overall repertoire of proteins that can bind in vivo. (+info)
Disordered T-cell development and T-cell malignancies in SCL LMO1 double-transgenic mice: parallels with E2A-deficient mice.
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The gene most commonly activated by chromosomal rearrangements in patients with T-cell acute lymphoblastic leukemia (T-ALL) is SCL/tal. In collaboration with LMO1 or LMO2, the thymic expression of SCL/tal leads to T-ALL at a young age with a high degree of penetrance in transgenic mice. We now show that SCL LMO1 double-transgenic mice display thymocyte developmental abnormalities in terms of proliferation, apoptosis, clonality, and immunophenotype prior to the onset of a frank malignancy. At 4 weeks of age, thymocytes from SCL LMO1 mice show 70% fewer total thymocytes, with increased rates of both proliferation and apoptosis, than control thymocytes. At this age, a clonal population of thymocytes begins to populate the thymus, as evidenced by oligoclonal T-cell-receptor gene rearrangements. Also, there is a dramatic increase in immature CD44(+) CD25(-) cells, a decrease in the more mature CD4(+) CD8(+) cells, and development of an abnormal CD44(+) CD8(+) population. An identical pattern of premalignant changes is seen with either a full-length SCL protein or an amino-terminal truncated protein which lacks the SCL transactivation domain, demonstrating that the amino-terminal portion of SCL is not important for leukemogenesis. Lastly, we show that the T-ALL which develop in the SCL LMO1 mice are strikingly similar to those which develop in E2A null mice, supporting the hypothesis that SCL exerts its oncogenic action through a functional inactivation of E proteins. (+info)