Functional analysis of Niemann-Pick disease type C family protein, NPC1a, in Drosophila melanogaster.

TitleFunctional analysis of Niemann-Pick disease type C family protein, NPC1a, in Drosophila melanogaster.
Publication TypeJournal Article
Year of Publication2019
AuthorsBialistoky, T, Manry, D, Smith, P, Ng, C, Kim, Y, Zamir, S, Moyal, V, Kalifa, R, Schedl, P, Gerlitz, O, Deshpande, G
JournalDevelopment
Volume146
Issue10
Date Published2019 May 15
ISSN1477-9129
Abstract

During embryonic gonad coalescence, primordial germ cells (PGCs) follow a carefully choreographed migratory route circumscribed by guidance signals towards somatic gonadal precursor cells (SGPs). In Drosophila melanogaster, SGP-derived Hedgehog (Hh), which serves as a guidance cue for the PGCs, is potentiated by mesodermally restricted HMGCoA-reductase (Hmgcr) and the ABC transporter Multi-drug-resistant-49 (Mdr49). Given the importance of cholesterol modification in the processing and long-distance transmission of the Hh ligand, we have analyzed the involvement of the Niemann-Pick disease type C-1a (NPC1a) protein, a cholesterol transporter, in germ cell migration and Hedgehog signaling. We show that mesoderm-specific inactivation of Npc1a results in germ cell migration defects. Similar to Mdr49, PGC migration defects in the Npc1a embryos are ameliorated by a cholesterol-rich diet. Consistently, reduction in Npc1a weakens the ability of ectopic HMG Coenzyme A reductase (Hmgcr) to induce germ cell migration defects. Moreover, compromising Npc1a levels influences Hh signaling adversely during wing development, a process that relies upon long-range Hh signaling. Last, doubly heterozygous embryos (Mdr49/Npc1a) display enhanced germ cell migration defects when compared with single mutants (Npc1a/+ or Mdr49/+), supporting cooperative interaction between the two.

DOI10.1242/dev.168427
Alternate JournalDevelopment
PubMed ID31092503