Composite signalling from Serrate and Delta establishes leg segments in Drosophila through Notch.
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The receptor protein NOTCH and its ligands SERRATE and DELTA are involved in many developmental processes in invertebrates and vertebrates alike. Here we show that the expression of the Serrate and Delta genes patterns the segments of the leg in Drosophila by a combination of their signalling activities. Coincident stripes of Serrate and Delta expressing cells activate Enhancer of split expression in adjacent cells through Notch signalling. These cells form a patterning boundary from which a putative secondary signal leads to the development of leg joints. Elsewhere in the tarsal segments, signalling by DELTA and NOTCH is necessary for the development of non-joint parts of the leg. We propose that these two effects result from different thresholds of NOTCH activation, which are translated into different downstream gene expression effects. We propose a general mechanism for creation of boundaries by Notch signalling. (+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)
p24 proteins and quality control of LIN-12 and GLP-1 trafficking in Caenorhabditis elegans.
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Mutations in the Caenorhabditis elegans sel-9 gene elevate the activity of lin-12 and glp-1, which encode members of the LIN-12/NOTCH family of receptors. Sequence analysis indicates SEL-9 is one of several C. elegans p24 proteins. Allele-specific genetic interactions suggest that reducing sel-9 activity increases the activity of mutations altering the extracellular domains of LIN-12 or GLP-1. Reducing sel-9 activity restores the trafficking to the plasma membrane of a mutant GLP-1 protein that would otherwise accumulate within the cell. Our results suggest a role for SEL-9 and other p24 proteins in the negative regulation of transport of LIN-12 and GLP-1 to the cell surface, and favor a role for p24 proteins in a quality control mechanism for endoplasmic reticulum-Golgi transport. (+info)
Antagonism of EGFR and notch signalling in the reiterative recruitment of Drosophila adult chordotonal sense organ precursors.
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The selection of Drosophila melanogaster sense organ precursors (SOPs) for sensory bristles is a progressive process: each neural equivalence group is transiently defined by the expression of proneural genes (proneural cluster), and neural fate is refined to single cells by Notch-Delta lateral inhibitory signalling between the cells. Unlike sensory bristles, SOPs of chordotonal (stretch receptor) sense organs are tightly clustered. Here we show that for one large adult chordotonal SOP array, clustering results from the progressive accumulation of a large number of SOPs from a persistent proneural cluster. This is achieved by a novel interplay of inductive epidermal growth factor-receptor (EGFR) and competitive Notch signals. EGFR acts in opposition to Notch signalling in two ways: it promotes continuous SOP recruitment despite lateral inhibition, and it attenuates the effect of lateral inhibition on the proneural cluster equivalence group, thus maintaining the persistent proneural cluster. SOP recruitment is reiterative because the inductive signal comes from previously recruited SOPs. (+info)
Presenilins in their infancy.
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Familial forms of Alzheimer's disease are caused by mutations in the genes encoding the presenilins, which are integral membrane proteins. Presenilins have been shown to interact with beta-amyloid precursor proteins and Notch receptors. Several recent studies have examined the role of presenilins in Notch processing. (+info)
Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development.
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The suggested role of Notch1 or its mutants in thymocyte differentiation and T cell tumorigenesis raises the question of how the different members of the Notch family influence distinct steps in T cell development and the role played by Notch ligands in the thymus. We report here that different Notch receptor-ligand partnerships may occur inside the thymus, as we observed differential expression of Notch1, 2 and 3 receptors, their ligands Jagged1 and 2, and downstream intracellular effectors hairy and Enhancer of Split homolog 1 (HES-1) and hairy and Enhancer of Split homolog 5 (HES-5), depending on ontogenetic stage and thymic cell populations. Indeed, while Jagged2 is expressed in both stromal cells and thymocytes, Jagged1 expression is restricted to stromal cells. Moreover, a differential distribution of Notch3, with respect to Notch1, was observed in distinct age-related thymocyte subsets. Finally, Notch3 was preferentially up-regulated in thymocytes, following the induction of their differentiation by interaction with thymic epithelial cells expressing the cognate Jagged1 and 2 ligands, suggesting that, besides Notch1, Notch3 may also be involved in distinct steps of thymocyte development. Our results suggest that the Notch signaling pathway is involved in a complex interplay of T cell developmental stages, as a consequence of the heterogeneity and specific expression of members of the Notch receptor family and their cognate ligands, in distinct thymic cell compartments. (+info)
Repression by Notch is required before Wingless signalling during muscle progenitor cell development in Drosophila.
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The larval muscles of Drosophila arise from the fusion of muscle founder cells, which give each individual muscle its identity, with myoblasts (reviewed in [1]). Muscle founder cells arise from the asymmetric division of muscle progenitor cells, each of which develops from a group of cells in the somatic mesoderm that express lethal of scute [2]. All the cells in a cluster can potentially form muscle progenitors, but owing to lateral inhibition, only one or two develop as such [2] [3] [4] [5]. Muscle progenitors, and the subsequent founder cells, then express transcription factors such as Kruppel, S59 and Even-skipped, which confer identity on the muscle [6] [7] [8]. Definition of some muscle progenitors, including three groups that express S59, depends on Wingless signalling [9]. Lateral inhibition requires Delta signalling through Notch and the transcription factor Suppressor of Hairless [3] [4] [5]. As the Wingless and lateral-inhibition signals are sequential [8], one might expect that muscle progenitors would fail to develop in the absence of Wingless signalling, regardless of the presence or absence of lateral-inhibition signalling. Here, we examine the development of the S59-expressing muscle progenitor cells in mutant backgrounds in which both Wingless signalling and lateral inhibition are disrupted. We show that progenitor cells failed to develop when both these processes were disrupted. Our analysis also reveals a repressive function of Notch, required before or concurrently with Wingless signalling, which is unrelated to its role in lateral inhibition. (+info)