Functional analysis of Niemann-Pick disease type C family protein, NPC1a, in Drosophila melanogaster
| Autor: | Paul Schedl, Diane Manry, Girish Deshpande, Rachel Kalifa, Victoria Moyal, Christopher Ng, Offer Gerlitz, Sol Zamir, Yunah Kim, Peyton Smith, Tzofia Bialistoky |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | Development. 146 |
| ISSN: | 1477-9129 0950-1991 |
| DOI: | 10.1242/dev.168427 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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