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Yorkie and Scalloped signaling regulates Notch-dependent lineage specification during Drosophila hematopoiesis.

ABSTRACT: Cellular microenvironments established by the spatial and temporal expression of specific signaling molecules are critical for both the maintenance and lineage-specific differentiation of progenitor cells. In Drosophila, a population of hematopoietic progenitors, or prohemocytes, within the larval lymph gland gives rise to three mature cell types: plasmatocytes, lamellocytes, and crystal cells. Removal of the secreted signaling molecules Hedgehog and PVF1 from the posterior signaling center (PSC), which acts as a niche, leads to a loss of progenitors and complete differentiation of the lymph gland. Here, we characterize a novel population of signaling cells within the lymph gland, distinct from the PSC, that are required for lineage-specific differentiation of crystal cells. We provide evidence that Yorkie and Scalloped, the Drosophila homologs of YAP and TEAD, are required in lineage-specifying cells to regulate expression of Serrate, the Notch ligand responsible for the initiation of the crystal cell differentiation program. Genetic manipulation of yorkie and scalloped in the lymph gland specifically alters Serrate expression and crystal cell differentiation. Furthermore, Serrate expression in lineage-specifying cells is eliminated in the lymph gland upon the immune response induced by wasp parasitization to ensure the proper differentiation of lamellocytes at the expense of crystal cells. These findings expand the roles for Yorkie/Scalloped beyond growth to encompass specific cell-fate determination in the context of blood development. Similar regulatory functions may extend to their homologs in vertebrate progenitor cell niches that are required for specifying cell fate.

SUBMITTER: Ferguson GB

PROVIDER: S-EPMC4256154 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Yorkie and Scalloped signaling regulates Notch-dependent lineage specification during Drosophila hematopoiesis.

Ferguson Gabriel B GB Martinez-Agosto Julian A JA

Current biology : CB 20141030 22

Cellular microenvironments established by the spatial and temporal expression of specific signaling molecules are critical for both the maintenance and lineage-specific differentiation of progenitor cells. In Drosophila, a population of hematopoietic progenitors, or prohemocytes, within the larval lymph gland gives rise to three mature cell types: plasmatocytes, lamellocytes, and crystal cells. Removal of the secreted signaling molecules Hedgehog and PVF1 from the posterior signaling center (PSC ...[more]

PMID: 25454586

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Project description:Somatic activating mutations in the Notch1 receptor result in the overexpression of activated Notch1, which can be tumorigenic. The goal of this study is to understand the molecular mechanisms underlying the phenotypic changes caused by the overexpression of ligand independent Notch 1 by using a tetracycline inducible promoter in an in vitro embryonic stem (ES) cells/OP9 stromal cells coculture system, recapitulating normal hematopoiesis. First, an in silico analysis of the promoters of Notch regulated genes (previously determined by microarray analysis) revealed that the motifs recognized by regulatory proteins known to mediate hematopoiesis were overrepresented. Notch 1 does not bind DNA but instead binds the CSL transcription factor to regulate gene expression. The in silico analysis also showed that there were putative CSL binding sites observed in the promoters of 28 out of 148 genes. A custom ChIP-chip array was used to assess the occupancy of CSL in the promoter regions of the Notch1 regulated genes in vivo and showed that 61 genes were bound by activated Notch responsive CSL. Then, comprehensive mapping of the CSL binding sites genome-wide using ChIP-seq analysis revealed that over 10,000 genes were bound within 10 kb of the TSS (transcription start site). The majority of the targets discovered by ChIP-seq belong to pathways that have been shown by others to crosstalk with Notch signaling. Finally, 83 miRNAs were significantly differentially expressed by greater than 1.5-fold during the course of in vitro hematopoiesis. Thirty one miRNA were up-regulated and fifty two were down-regulated. Overexpression of Notch1 altered this pattern of expression of microRNA: six miRNAs were up-regulated and four were down regulated as a result of activated Notch1 overexpression during the course of hematopoiesis. Time course analysis of hematopoietic development revealed that cells with Notch 1 overexpression mimic miRNA expression of cells in a less mature stage, which is consistent with our previous biological characterization.

Dataset Information

Yorkie and Scalloped signaling regulates Notch-dependent lineage specification during Drosophila hematopoiesis.

Publications

Yorkie and Scalloped signaling regulates Notch-dependent lineage specification during Drosophila hematopoiesis.

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