Mon1 is an evolutionarily conserved protein involved in the conversion of Rab5 positive early endosomes to late endosomes through the recruitment of Rab7. We have identified a role for Drosophila Mon1 in regulating glutamate receptor levels at the larval neuromuscular junction. We generated mutants in Dmon1 through P-element excision. These mutants are short-lived with strong motor defects. At the synapse, the mutants show altered bouton morphology with several small supernumerary or satellite boutons surrounding a mature bouton; a significant increase in expression of GluRIIA and reduced expression of Bruchpilot. Neuronal knockdown of Dmon1 is sufficient to increase GluRIIA levels, suggesting its involvement in a presynaptic mechanism that regulates postsynaptic receptor levels. Ultrastructural analysis of mutant synapses reveals significantly smaller synaptic vesicles. Overexpression of vglut suppresses the defects in synaptic morphology and also downregulates GluRIIA levels in Dmon1 mutants, suggesting that homeostatic mechanisms are not affected in these mutants. We propose that DMon1 is part of a presynaptically regulated transsynaptic mechanism that regulates GluRIIA levels at the larval neuromuscular junction.
Monensin-sensitive 1 (Mon1) is an endocytic regulator that participates in the conversion of Rab5-positive early endosomes to Rab7-positive late endosomes. In Drosophila, loss of mon1 leads to sterility as the mon1 mutant females have extremely small ovaries with complete absence of late stage egg chambersa phenotype reminiscent of mutations in the insulin pathway genes. Here, we show that expression of many Drosophila insulin-like peptides (ILPs) is reduced in mon1 mutants and feeding mon1 adults an insulin-rich diet can rescue the ovarian defects. Surprisingly, however, mon1 functions in the tyramine/ octopaminergic neurons (OPNs) and not in the ovaries or the insulinproducing cells (IPCs). Consistently, knockdown of mon1 in only the OPNs is sufficient to mimic the ovarian phenotype, while expression of the gene in the OPNs alone can 'rescue' the mutant defect. Last, we have identified ilp3 and ilp5 as critical targets of mon1. This study thus identifies mon1 as a novel molecular player in the brain-gonad axis and underscores the significance of inter-organ systemic communication during development.
Folded gastrulation (Fog) is a secreted ligand that signals through the G-protein-coupled receptors Mist and Smog and the G-protein Concertina to activate downstream effectors to elicit cell-shape change during gastrulation. In the embryonic central nervous system (CNS), Fog has roles in axon guidance and glial morphogenesis. However, the elements of the pathway as well as mechanisms required for transducing the signal in this context have not been determined. We find that while Concertina is essential for Fog signaling, Mist is dispensable and Smog, surprisingly, functions as a negative regulator of the pathway in the CNS. Interestingly Heartless, a fibroblast growth factor receptor, also functions as a negative regulator. Furthermore, both Heartless and Smog interact in a synergistic manner to regulate Fog signaling. Our results thus identify Heartless and Smog as part of a common regulatory pathway that functions to restrict Fog signaling in the embryonic CNS and highlights the context-specific role for Fog receptors during development.
G-protein coupled receptor (GPCR) signaling triggered by Folded gastrulation (Fog) is one of the pathways known to regulate glial organization and morphogenesis in the embryonic CNS in Drosophila. Fog is best known for its role in epithelial morphogenesis during gastrulation. Here, the signaling pathway includes GPCRs Mist and Smog and the G-Protein Concertina (Cta) which activate downstream effectors to bring about cytoskeletal changes essential for cell shape changeIn this study, we identify molecular players that mediate and serve as important regulators of Fog signaling in the embryonic CNS. We find that while Cta is essential for Fog signaling neither receptors, Mist nor Smog mediates signaling in the CNS. On the contrary, we find that Smog functions as a negative regulator of the pathway. Surprisingly, Heartless which encodes a fibroblast growth factor receptor, also functions as a negative regulator of Fog signaling. Further, we find that both heartless and smog interact in a synergistic manner to regulate Fog signaling.This study thus identifies novel regulators of Fog signaling that may play an important role in fine-tuning the pathway to control cell morphogenesis. It also suggests the likelihood of there being multiple receptors for Fog that mediate and regulate signaling in a context specific manner.Author SummaryIn Drosophila, Folded gastrulation (Fog) functions as ligand that signals via GPCRs to regulate cell shape during gastrulation -one of the earliest events in embryogenesis. Here, Fog signals via receptors Mist and Smog to activate the G-protein Concertina to elicit change in cell shape. In the embryonic central nervous system (CNS) this pathway regulates shape and organization of glia important for functions such as insulation of neurons and synapses.The mechanism of Fog signal transduction in the CNS and its regulation is not well understood. We have sought to address these questions in our study. We find that Concertina is an essential factor for Fog signaling in the CNS but interestingly Mist is not. In contrast, Smog functions as a negative regulator such that loss of Smog enhances Fog signaling. A similar role is played by the receptor tyrosine kinase-Heartless. Interestingly, we find that Smog and Heartless interact as part of a common genetic network to regulate Fog signaling. Our results thus provide novel insights into the regulation of Fog signaling and shed light on how signaling can be fine-tuned in a context dependent manner to control cell shape change which plays a critical role during development and organ formation.
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