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Development. 2019 May 15;146(10). pii: dev168427. doi: 10.1242/dev.168427.

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

Author information

1
Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel.
2
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA.
3
Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada (IMRIC), The Hebrew University-Hadassah Medical School, Jerusalem, Israel gdeshpan@princeton.edu offerg@ekmd.huji.ac.il.
4
Department of Molecular Biology, Princeton University, Princeton, NJ 08540, USA gdeshpan@princeton.edu offerg@ekmd.huji.ac.il.

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.

KEYWORDS:

Cell migration; Drosophila melanogaster; Embryogenesis; Primordial germ cells

PMID:
31092503
PMCID:
PMC6550021
[Available on 2020-05-15]
DOI:
10.1242/dev.168427

Conflict of interest statement

Competing interestsThe authors declare no competing or financial interests.

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