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

Author(s): Bialistoky, Tzofia; Manry, Diane; Smith, Peyton; Ng, Christopher; Kim, Yunah; et al

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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.
Publication Date: 15-May-2019
Citation: Bialistoky, Tzofia, Manry, Diane, Smith, Peyton, Ng, Christopher, Kim, Yunah, Zamir, Sol, Moyal, Victoria, Kalifa, Rachel, Schedl, Paul, Gerlitz, Offer, Deshpande, Girish. (2019). Functional analysis of Niemann-Pick disease type C family protein, NPC1a, in Drosophila melanogaster. Development (Cambridge, England), 146 (10), 10.1242/dev.168427
DOI: doi:10.1242/dev.168427
ISSN: 0950-1991
EISSN: 1477-9129
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Development (Cambridge, England)
Version: Final published version. This is an open access article.

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