Niemann-Pick Disease Type C family protein, NPC1a, in embryonic germ cell migration and Hedgehog Signaling in Drosophila melanogaster

Abstract

Proper migration of Primordial Germ Cells (PGCs) in Drosophila melanogaster embryos requires a series of attractive and repulsive cues that guide the PGCs to the somatic gonadal precursor cells (SGPs). During the course of embryogenesis, PGCs follow a stereotypical migratory route across different cell layers in order to travel towards and associate with SGPs in the gonadal mesoderm. Recent observations have suggested that the signaling ligand Hedgehog (Hh), the biosynthetic enzyme HMGCoA reductase (Hmgcr), and the ABC transporter multi-drug-resistant-49 (Mdr49) all have roles during germ cell migration pathway, but the precise mechanism underlying their action has remained elusive. It was recently proposed that Mdr49 functions in hh signaling likely via its involvement in the cholesterol transport. Given the importance of cholesterol in the processing and long-distance transmission of the Hh ligand, we have undertaken analysis of crucial players responsible for cholesterol transport. In this study, we have explored the involvement of the well documented cholesterol transporter Niemann-Pick Disease Type C 1a (npc1a) in germ cell migration and Hedgehog signaling. Previous studies have established that hmgcr potentiates Hh signaling by promoting its release and/or transmission from the Hh synthesizing cells and can thus facilitate PGC migration towards SGPs. Here we show that inactivation of npc1a results in germ cell migration defects. Importantly, reduction in npc1a compromises Hh signaling during wing development, another patterning event that relies upon long-range Hh signaling. Supporting the conclusion that hmgcr dependent potentiation of Hh requires npc1a activity, reduction in npc1a weakens the ability of ectopic hmgcr to induce germ cell migration defects. Taken together these data suggest that Npc1a functions in conjunction with Mdr49 in the SGPs to regulate the activity of Hh to function as a guidance cue for the migrating PGCs.