The homeobox gene Caudal regulates constitutive local expression of antimicrobial peptide genes in Drosophila epithelia.
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ABSTRACT:
SUBMITTER: Ryu JH
PROVIDER: S-EPMC303351 | biostudies-other | 2004 Jan
REPOSITORIES: biostudies-other
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Project description:The caudal-related homeobox transcription factors are required for the normal development and differentiation of intestinal cells. Recent reports indicate that misregulation of homeotic gene expression is associated with gastrointestinal cancer in mammals. However, the molecular mechanisms that regulate expression of the caudal-related homeobox genes are poorly understood. In this study, we have identified a DNA replication-related element (DRE) in the 5' flanking region of the Drosophila caudal gene. Gel-mobility shift analysis reveals that three of the four DRE-related sequences in the caudal 5'-flanking region are recognized by the DRE-binding factor (DREF). Deletion and site-directed mutagenesis of these DRE sites results in a considerable reduction in caudal gene promoter activity. Analyses with transgenic flies carrying a caudal-lacZ fusion gene bearing wild-type or mutant DRE sites indicate that the DRE sites are required for caudal expression in vivo. These findings indicate that DRE/DREF is a key regulator of Drosophila caudal homeobox gene expression and suggest that DREs and DREF contribute to intestinal development by regulating caudal gene expression.
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Project description:The differentiation efficiency of adult stem cells undergoes a significant decline in aged animals, which is closely related to the decline in organ function and age-associated diseases. However, the underlying mechanisms that ultimately lead to this observed decline of the differentiation efficiency of stem cells remain largely unclear. This study investigated Drosophila midguts and identified an obvious upregulation of caudal (cad), which encodes a homeobox transcription factor. This factor is traditionally known as a central regulator of embryonic anterior-posterior body axis patterning. This study reports that depletion of cad in intestinal stem/progenitor cells promotes quiescent intestinal stem cells (ISCs) to become activate and produce enterocytes in the midgut under normal gut homeostasis conditions. However, overexpression of cad results in the failure of ISC differentiation and intestinal epithelial regeneration after injury. Moreover, this study suggests that cad prevents intestinal stem/progenitor cell differentiation by modulating the Janus kinase/signal transducers and activators of the transcription pathway and Sox21a-GATAe signaling cascade. Importantly, the reduction of cad expression in intestinal stem/progenitor cells restrained age-associated gut hyperplasia in Drosophila. This study identified a function of the homeobox gene cad in the modulation of adult stem cell differentiation and suggested a potential gene target for the treatment of age-related diseases induced by age-related stem cell dysfunction.
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Project description:The innate immune response in Drosophila involves the inducible expression of antimicrobial peptide genes mediated by the Toll and IMD signaling pathways. Dorsal and DIF act downstream of Toll, whereas Relish acts downstream of IMD to regulate target gene expression. Dorsal, DIF, and Relish are NF-kappaB-related transcription factors and function as obligate dimers, but it is not clear how the various dimer combinations contribute to the innate immune response. We systematically examined the dimerization tendency of these proteins through the use of transgenic assays. The results show that all combinations of homo- and heterodimers are formed, but with varying degrees of efficiency. The formation of the DIF-Relish heterodimer is particularly interesting because it may mediate signaling for the seemingly independent Toll and IMD pathways. By incorporating a flexible peptide linker, we specifically tested the functions of the DIF;Relish (a ; sign represents the peptide linker) linked heterodimer. Our results demonstrate that the linked heterodimer can activate target genes of both the Toll and IMD pathways. The DIF and Relish complex is detectable in whole animal extracts, suggesting that this heterodimer may function in vivo to increase the spectrum and level of antimicrobial peptide production in response to different infections.
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