[Show abstract][Hide abstract] ABSTRACT: The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis.
[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.
Journal of Genetics and Genomics 06/2014; 41(6). DOI:10.1016/j.jgg.2014.04.005 · 3.59 Impact Factor
[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.
[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.