[Show abstract][Hide abstract] ABSTRACT: Author Summary
Effective tissue homeostasis requires a proper balance between the removal of dead cells and production of new cells. Due to environmental challenges, the Drosophila midgut epithelial cells are damaged from time to time and intestinal stem cells (ISC) can accelerate their proliferative rate to replace the lost midgut epithelium. The JAK/STAT pathway plays essential roles in these progresses. Upon damage, Upd ligands produced by dying enterocytes (ECs) activate JAK/STAT signaling in ISCs to promote their proliferation and differentiation. However, after damage how JAK/STAT signaling is switched from a highly active state to a homeostatic state is not yet fully understood. In this study, we identified the leucine rich repeats (LRR) protein Windpipe (Wdp) as a novel negative feedback regulator of JAK/STAT signaling during intestinal development. Wdp expression was induced by high levels of JAK/STAT signaling in intestines. And loss of Wdp leads to midgut homeostasis loss and increased ISC proliferation. Furthermore, we found Wdp in turn negatively regulates JAK/STAT signaling activity through promoting Domeless receptor endocytosis and lysosomal degradation. In this way, high levels of JAK/STAT signaling is switched off by Wdp, which ensure ISCs return to the homeostatic state after tissue damage.
[Show abstract][Hide abstract] ABSTRACT: The highly conserved Notch signaling is precisely regulated at different steps in a series of developmental events. However, little is known about the regulation of Notch receptor at transcriptional level. Here, we demonstrate that dBrms1 is involved in regulating Notch signaling in Drosophila wing. We show that knockdown of dBrms1 by RNA interference (RNAi) in wing disc suppresses the expression of Notch signaling target genes Wingless (Wg), Cut and Enhancer of split m8 [E(spl)m8]. Consistently, the levels of Wg and Cut are reduced in the dBrms1 mutant clones. Importantly, loss of dBrms1 leads to significant reduction of Notch proteins. Furthermore, depletion of dBrms1 results in apparent downregulation of Notch transcription in the wing disc. Moreover, we find that dBrms1 is functionally conserved with human Breast cancer metastasis suppressor 1 like (hBRMS1L) in the modulation of Notch signaling. Taken together, our data provide important insights into the biological function of dBrms1 in regulating Notch signaling.
Full-text · Article · Jun 2014 · Journal of Genetics and Genomics
[Show abstract][Hide abstract] ABSTRACT: Hedgehog (Hh) proteins act as morphogens in a variety of developmental contexts to control cell fates and growth in a concentration-dependent manner. Therefore, secretion, distribution, and reception of Hh proteins must be tightly regulated and deregulation of these processes contributes to numerous human diseases. Brother of ihog (Boi) and its close relative Ihog (Interference hedgehog) are cell surface proteins that act as Hh co-receptors required for Hh signaling response and cell-surface maintenance of Hh protein. MicroRNAs (miRNAs) are a group of widely expressed 21-23 nucleotides non-coding RNAs that repress gene function through interactions with target mRNAs. Here, we have identified a novel miRNA, miR-932, as an important regulator for Boi. We show that overexpression of miR-932 in the wing disc can enhance Hh signaling strength, but reduce its signaling range, a phenotype similar to that of boi knockdown. In both in vivo sensor assay and in vitro luciferase assay, miR-932 can suppress Boi by directly binding to its 3'UTR. Meanwhile, down-regulation of miR-932 by sponge elevates the protein level of Boi, confirming that miR-932 is an in vivo regulator of Boi expression. Further, we demonstrate that miR-932 can block Hh signaling when co-expressed with ihog-RNAi. Moreover, we find that other predicted miRNAs of Boi fail to suppress it as strong as miR-932. Taken together, our data demonstrate that miR-932 can modulate Hh activity by specifically targeting Boi in Drosophila, illustrating the important roles of miRNAs in fine regulation of the Hh signaling pathway.
No preview · Article · Feb 2013 · Developmental Biology
[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are endogenous small non-coding RNAs that post-transcriptionally regulate gene expression in eukaryotes. In Drosophila melanogaster, up to 240 miRNAs have been identified by computational methods or experimental approaches. However, most of their biological functions are still unknown. Here, we identified miR-960 as a suppressor of Hedgehog (Hh) signaling pathway. Ectopic miR-960 obviously represses the expression levels of target genes. This activity is mediated by direct inhibition of Smoothened (Smo), Costal-2 (Cos2) and Fused (Fu), which are essential signaling transduction components of Hh pathway. Through in vivo sensor assay and in vitro luciferase assay, we found miR-960 directly binds to the 3'UTR of smo, cos2 and fu mRNAs to block their translation. Additionally, we demonstrated that miR-960 cannot suppress Wg and Dpp signaling pathways. Together, our results indicate that miR-960 can specifically suppress Hh pathway by directly targeting three important signaling transducers Smo, Cos2 and Fu.
No preview · Article · Feb 2013 · Cellular Signalling