The role of Niemann-Pick type C2 in zebrafish embryonic development

被引:7
作者
Tseng, Wei-Chia [1 ]
Escauriza, Ana J. Johnson [1 ]
Tsai-Morris, Chon-Hwa [2 ]
Feldman, Benjamin [2 ]
Dale, Ryan K. [3 ]
Wassif, Christopher A. [1 ]
Porter, Forbes D. [1 ]
机构
[1] Eunice Kennedy Shriver NICHHD, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA
[2] Eunice Kennedy Shriver NICHHD, Zebrafish Core, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA
[3] Eunice Kennedy Shriver NICHHD, Bioinformat & Sci Programming Core, Dept Hlth & Human Serv, NIH, Bethesda, MD 20892 USA
来源
DEVELOPMENT | 2021年 / 148卷 / 07期
关键词
Zebrafish; Niemann-Pick type C; Niemann-Pick type C2; Npc2; Notch3; Cholesterol; DISEASE TYPE-C; VASCULAR INTEGRITY; IN-VIVO; CHOLESTEROL; MODEL; NOTCH3; GENES; STORAGE; PATHWAY; NPC1;
D O I
10.1242/dev.194258
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 that 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, and reduction of cellular cholesterol bioavailability. Zygotic null nperilin 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 and no circulating blood cells, and died by 72 hpf. RNA-seq analysis conducted on 30 hpf npc2(m/m) and MZnpc2(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 MZnpc2(m/m) zebrafish.
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页数:14
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