PUBLICATION

Ercc2/Xpd deficiency results in failure of digestive organ growth in zebrafish with elevated nucleolar stress

Authors: Ma, J., Shao, X., Geng, F., Liang, S., Yu, C., Zhang, R.
ID: ZDB-PUB-220907-37
Date: 2022
Source: iScience 25: 104957 (Journal)
Registered Authors: Zhang, Ruilin
Keywords: Animal physiology, biological sciences, cell biology, molecular biology
Datasets: GEO:GSE184305
MeSH Terms: none
PubMed: 36065184 Full text @ iScience

Abstract

Mutations in ERCC2/XPD helicase, an important component of the TFIIH complex, cause distinct human genetic disorders which exhibit various pathological features. However, the molecular mechanisms underlying many symptoms remain elusive. Here, we have shown that Ercc2/Xpd deficiency in zebrafish resulted in hypoplastic digestive organs with normal bud initiation but later failed to grow. The proliferation of intestinal endothelial cells was impaired in ercc2/xpd mutants, and mitochondrial abnormalities, autophagy, and inflammation were highly induced. Further studies revealed that these abnormalities were associated with the perturbation of rRNA synthesis and nucleolar stress in a p53-independent manner. As TFIIH has only been implicated in RNA polymerase I-dependent transcription in vitro, our results provide the first evidence for the connection between Ercc2/Xpd and rRNA synthesis in an animal model that recapitulates certain key characteristics of ERCC2/XPD-related human genetic disorders, and will greatly advance our understanding of the molecular pathogenesis of these diseases.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
anxa5b	AB	standard conditions	Day 5	swim bladder	ISH	Fig. 1
anxa5b	ercc2^{whu312/whu312}	standard conditions	Day 5	swim bladder	ISH	Fig. 1
cdh17	AB	standard conditions	Day 5	pronephric duct	IHC	Fig. 1
cdh17	ercc2^{whu312/whu312}	standard conditions	Day 5	pronephric duct	IHC	Fig. 1
cxcl8b.1	AB	standard conditions	Days 7-13	whole organism	RTPCR	Fig. 5
cxcl8b.1	AB	standard conditions	Day 5	whole organism	RTPCR	Fig. 5
cxcl8b.1	ercc2^{whu312/whu312}	standard conditions	Day 5	whole organism	RTPCR	Fig. 5
cxcl8b.1	ercc2^{whu312/whu312}	standard conditions	Days 7-13	whole organism	RTPCR	Fig. 5
ddx4	ercc2^{whu312/whu312}	standard conditions	Day 5	primordial germ cell	ISH	Fig. 1
DsRed	ercc2^whu312/+; gz15Tg	standard conditions	Day 4	liver	IFL	Fig. 3

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
ercc2^whu312/+; gz15Tg	standard conditions	Day 5	liver DsRed expression decreased amount, abnormal	Fig. 1
ercc2^whu312/+; gz15Tg	standard conditions	Day 5	liver DsRed expression decreased distribution, abnormal	Fig. 1
ercc2^whu312/+; gz15Tg	standard conditions	Day 5	pancreas DsRed expression decreased amount, abnormal	Fig. 1
ercc2^whu312/+; gz15Tg	standard conditions	Day 5	pancreas DsRed expression decreased distribution, abnormal	Fig. 1
ercc2^{whu312/whu312}	standard conditions	Protruding-mouth	intestine fabp2 expression decreased amount, abnormal	Fig. 3
ercc2^{whu312/whu312}	standard conditions	Protruding-mouth	intestine fabp2 expression decreased distribution, abnormal	Fig. 3
ercc2^{whu312/whu312}	standard conditions	Protruding-mouth	intestine morphology, normal	Fig. 1
ercc2^{whu312/whu312}	standard conditions	Protruding-mouth	liver morphology, normal	Fig. 1
ercc2^{whu312/whu312}	standard conditions	Protruding-mouth	pancreas prss1 expression decreased amount, abnormal	Fig. 3
ercc2^{whu312/whu312}	standard conditions	Protruding-mouth	pancreas prss1 expression decreased distribution, abnormal	Fig. 3

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion
ia3Tg	Tg(-3.5nkx2.2a:GFP)	Transgenic Insertion
s843Tg	Tg(kdrl:EGFP)	Transgenic Insertion
sqet33J1Et	Et(krt4:EGFP)	Transgenic Insertion
whu312		Small Deletion	ercc2
zdf1		Point Mutation	tp53

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ercc2	CRISPR1-ercc2	CRISPR

Fish

Fish
AB
ercc2^whu312/+
ercc2^whu312/+; gz15Tg
ercc2^whu312/+; gz15Tg/+
ercc2^{whu312/whu312}
ercc2^{whu312/whu312}
ercc2^{whu312/whu312}; gz15Tg
ercc2^{whu312/whu312}; ia3Tg
ercc2^{whu312/whu312}; s843Tg
ercc2^{whu312/whu312}; sqet33J1Et

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-ercc2	monoclonal		IgG	Rabbit
Ab1-fbl	monoclonal	fbl	IgG1	Mouse
Ab1-mt-co1	monoclonal		IgG2a	Mouse
Ab1-ncl	polyclonal		IgG	Rabbit
Ab3-map1lc3b	polyclonal	map1lc3b	IgG	Rabbit
Ab4-h3	polyclonal		IgG	Rabbit
Ab7-h2afx	polyclonal		IgG	Rabbit

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Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
DsRed	EFG	DsRed
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Ma et al., 2022 ZDB-PUB-220907-37 PMID:36065184

Ercc2/Xpd deficiency results in failure of digestive organ growth in zebrafish with elevated nucleolar stress

Ma et al., 2022

ZDB-PUB-220907-37
PMID:36065184