Open AccessThe role of Niemann-Pick type C2 in zebrafish embryonic development
Author(s) -
Wei-Chia Tseng,
Ana J Johnson Escauriza,
ChonHwa TsaiMorris,
Benjamin Feldman,
Ryan K. Dale,
Christopher A. Wassif,
Forbes D. Porter
Publication year - 2021
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.15
H-Index - 36
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.194258
Subject(s) - npc1 , zebrafish , biology , microbiology and biotechnology , endosome , embryonic stem cell , phenotype , lysosome , morpholino , cholesterol , gene , endocrinology , genetics , biochemistry , enzyme , intracellular
Niemann-Pick disease type C (NPC) is a rare, fatal, neurodegenerative lysosomal disease caused by mutations of either NPC1 or NPC2 . NPC2 is a soluble lysosomal protein which functions in coordination with NPC1 to efflux cholesterol from the lysosomal compartment. Mutations of either gene result in the accumulation of unesterified cholesterol and other lipids in the late endosome/lysosome, while reducing cellular cholesterol bioavailability. Zygotic null npc2 m/m zebrafish showed significant unesterified cholesterol accumulation at larval stages, a reduction in body size, and motor and balance defects in adulthood. However, the phenotype at embryonic stages was milder than expected, suggesting a possible role of maternal Npc2 in embryonic development. Maternal-zygotic npc2 m/m zebrafish exhibited significant developmental defects including defective otic vesicle development/absent otoliths, abnormal head/brain development, curved/twisted body axes, no circulating blood cells, and died by 72 hpf. RNA-seq analysis conducted on 30 hpf npc2 + /m and MZ npc2 m/m embryos revealed a significant reduction in the expression of notch3 and other downstream genes in the Notch signaling pathway, suggesting that impaired Notch3 signaling underlies aspects of the developmental defects observed in MZ npc2 m/m zebrafish.