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

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.

• Authors: Tzofia Bialistoky, Diane Manry, Peyton Smith, Christopher Ng, Yunah Kim, Sol Zamir, Victoria Moyal, Rachel Kalifa, Paul Schedl, Offer Gerlitz, Girish Deshpande
• Journal: Development (Cambridge, England) (Development) Vol. 146 Issue 10 (05 15 2019) ISSN: 1477-9129 [Electronic] England
• PMID: 31092503 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019. Published by The Company of Biologists Ltd.

Chemical References

• Drosophila Proteins
• Membrane Proteins
• Niemann-Pick C1 Protein
• Npc1a protein, Drosophila

Topics

• Animals
• Cell Movement (genetics, physiology)
• Drosophila Proteins (genetics, metabolism)
• Drosophila melanogaster
• Gene Expression Regulation, Developmental (genetics, physiology)
• Germ Cells (metabolism)
• Heterozygote
• Membrane Proteins (genetics, metabolism)
• Neurons (metabolism)
• Niemann-Pick C1 Protein
• Signal Transduction (genetics, physiology)