PUBLICATION

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

Authors

Tseng, W.C., Johnson Escauriza, A.J., Tsai-Morris, C.H., Feldman, B., Dale, R.K., Wassif, C.A., Porter, F.D.

ID

ZDB-PUB-210317-6

Date

2021

Source

Development (Cambridge, England) 148(7): (Journal)

Registered Authors

Feldman, Benjamin, Porter, Forbes, Tseng, Wei-Chia, Wassif, Christopher A.

Keywords

Cholesterol, Niemann-Pick type C, Niemann-Pick type C2, Notch3, Npc2, Zebrafish

Datasets

GEO:GSE161867

MeSH Terms

Receptor, Notch3/genetics
Receptor, Notch3/metabolism
Larva/anatomy & histology
Animals
Lysosomes/metabolism
Membrane Proteins/genetics
Membrane Proteins/metabolism
Gene Expression Regulation, Developmental
Embryonic Development
Endosomes/metabolism
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism*
Niemann-Pick Disease, Type C/genetics*
Niemann-Pick Disease, Type C/metabolism*
Cholesterol/metabolism
Zebrafish/anatomy & histology
Zebrafish/embryology
Zebrafish/genetics*
Zebrafish/metabolism*
Biological Transport

(all 20)

PubMed

33722902 Full text @ Development

Abstract

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 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.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Anatomy	Assay	Figure
npc2.1^y536/+ (EKW)	standard conditions	Prim-15	brain	ISH	Fig. 10
npc2.1^y536/+ (EKW)	standard conditions	Prim-15	otic vesicle	ISH	Fig. 10
npc2.1^y536/+ (EKW)	standard conditions	Prim-15	trunk dorsal margin	ISH	Fig. 10
npc2.1^y536/y536 (EKW)	standard conditions	Prim-15	brain	ISH	Fig. 10
npc2.1^y536/y536 (EKW)	standard conditions	Prim-15	otic vesicle	ISH	Fig. 10
npc2.1^y536/y536 (EKW)	standard conditions	Prim-15	trunk dorsal margin	ISH	Fig. 10
npc2.1^y536/+ (EKW)	standard conditions	Prim-15	central nervous system	ISH	Fig. S8
npc2.1^y536/y536 (EKW)	standard conditions	Prim-15	central nervous system	ISH	Fig. S8
npc2.1^y536/+ (EKW)	standard conditions	Prim-15	brain	ISH	Fig. 10
npc2.1^y536/+ (EKW)	standard conditions	Prim-15	otic vesicle	ISH	Fig. 10

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
EKW	chemical treatment: amphiphile	Prim-15	blood circulation disrupted, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	brain decreased size, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	head decreased size, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	otolith absent, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	otolith decreased size, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	post-vent region curved dorsal, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	post-vent region curved lateral, abnormal	Fig. 8
EKW	chemical treatment: amphiphile	Prim-15	post-vent region curved ventral, abnormal	Fig. 8
npc1^hg37/hg37 (EKW)	standard conditions	Prim-15	blood circulation disrupted, abnormal	Fig. S11
npc1^hg37/hg37 (EKW)	standard conditions	Prim-15	brain decreased size, abnormal	Fig. S11

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Mutations / Transgenics

Allele	Type	Affected Genomic Region
hg37	Indel	npc1
y536	Small Deletion	npc2.1
y537	Small Deletion	npc2.1

Human Disease / Model

Human Disease	Fish	Conditions	Evidence
Niemann-Pick disease type C2			TAS

Sequence Targeting Reagents

Target	Reagent	Reagent Type
npc2.1	CRISPR1-npc2.1	CRISPR

Fish

Fish
EKW
npc1^hg37/hg37 (EKW)
npc1^hg37/hg37 (EKW)
npc1^hg37/+ (EKW)
npc2.1^y536/+ (EKW)
npc2.1^y536/y536 (EKW)
npc2.1^y536/y536 (EKW)
npc2.1^y537/+ (EKW)
npc2.1^y537/y537 (EKW)
npc2.1^y537/y537 (EKW)

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Antibodies

Orthology

Engineered Foreign Genes

Mapping

Tseng et al., 2021 ZDB-PUB-210317-6 PMID:33722902

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

Tseng et al., 2021

ZDB-PUB-210317-6
PMID:33722902