Rab converter DMon1 constitutes a novel node in the brain-gonad axis essential for female germline maturation

Abstract

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 (Dmon1) leads to sterility. The Dmon1 mutant females have extremely small ovaries with complete absence of late stage egg chambers-a phenotype reminiscent of mutations in the insulin pathway genes. Consistently, we find that expression of many Drosophila insulin-like peptides (Dilps) is down regulated in Dmon1 mutants. Conversely, feeding an insulin-rich diet can rescue the ovarian defects induced by the loss of Dmon1.\n\nSurprisingly however, Dmon1 is required in the tyramine/octopaminergic neurons (OPNs) and not in the ovaries or the insulin producing cells (IPCs). Thus, knockdown of Dmon1 in just the OPNs is sufficient to mimic the ovarian phenotype while expression of Dmon1 in the OPNs alone, is sufficient to rescue the mutant defect.\n\nLastly, we have identified dilp5 as a critical target of Dmon1. Both, protein and mRNA levels of Dilp5 levels are reduced in Dmon1 mutants and IPC-specific dilp5 over expression can ameliorate the Dmon1 dependent sterility defect. The study thus identifies Dmon1 as a novel molecular player in the brain-gonad axis and underscores the significance of inter-organ systemic communication during development.\n\nSignificance Statement Functional significance of the long-distance systemic communication during organogenesis has emerged as a major area of enquiry. We have focused our attention on an endocytic regulator DMon1, that appears to participate in a remote control type of mechanism. We report a novel tripartite circuitry that involves Dmon1 activity in Octopaminergic neurons, its influence on insulin production in the insulin producing cells (IPCs) which, in turn, is required for the progression of oogenesis. Our results document a spatially remote non-autonomous control mechanism involving neuronal cross-talk that orchestrates developmental regulation of oogenesis. Importantly our data provide a unique example of how distinct neuronal hubs can engineer metabolic pathways underlying growth/differentiation and highlight the importance of systemic regulation of organogenesis.