PUBLICATION

LRH-1 senses signaling from phosphatidylcholine to regulate the expansion growth of digestive organs via synergy with Wnt/β-catenin signaling in zebrafish

Authors

Zhai, G., Song, J., Shu, T., Yan, J., Jin, X., He, J., Yin, Z.

ID

ZDB-PUB-170624-12

Date

2017

Source

Journal of genetics and genomics = Yi chuan xue bao 44(6): 307-317 (Journal)

Registered Authors

He, Jiangyan, Yan, Junjun, Yin, Zhan

Keywords

Development, LRH-1, Phosphatidylcholine, Wnt/β-catenin signaling, Zebrafish

MeSH Terms

Animals
Digestion*
Endoderm/embryology
Gene Expression Regulation, Developmental
Organogenesis/genetics
Phosphatidylcholines/metabolism*
Receptors, Cytoplasmic and Nuclear/metabolism*
Wnt Signaling Pathway*
Zebrafish/embryology
Zebrafish/genetics
Zebrafish/growth & development*
Zebrafish/metabolism*
Zebrafish Proteins/metabolism*

(all 13)

PubMed

28642062 Full text @ J. Genet. Genomics

Abstract

Liver receptor homolog-1 (LRH-1) is an orphan nuclear receptor that is critical for the growth and proliferation of cancer cells and other biological processes, including lipid transportation and metabolism, sexual determination and steroidogenesis. However, because homozygous lrh-1^-/- mice die in utero, the regulatory mechanisms involved in embryonic development mediated by this receptor are poorly understood. In the present study, we performed transcription activator-like effector nuclease (TALEN)-mediated loss-of-function assays, taking advantage of zebrafish external fertilization, to investigate the function of lrh-1. The digestive organs were affected by lrh-1 depletion as a result of cell-cycle arrest (at the checkpoint of G1 to S phase), but not cell apoptosis. Biochemical analysis revealed that LRH-1 augments the transcriptional activity of β-catenin 1 and 2 via physical interactions. Screening the specific ligand(s) sensed by LRH-1 during organogenesis revealed that phosphatidylcholine (PC), a potential ligand, is the upstream target of LRH-1 during endoderm development. These data provide evidence for the crosstalk between the PC/LRH-1 and Wnt/β-catenin signaling pathways during the expansion growth of endoderm organs.

Genes / Markers

Marker	Marker Type	Name
ccnd1	GENE	cyclin D1
ccne2	GENE	cyclin E2
chrd	GENE	chordin
cp	GENE	ceruloplasmin
cpa4	GENE	carboxypeptidase A4
ctnnb1	GENE	catenin (cadherin-associated protein), beta 1
ctnnb2	GENE	catenin, beta 2
dkk1b	GENE	dickkopf WNT signaling pathway inhibitor 1b
ela2	GENE	elastase 2
eve1	GENE	even-skipped-like1

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Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ccnd1	nr5a2^{ihb193/ihb193}	standard conditions	Day 4	intestine	ISH	Fig. 4
ccnd1	nr5a2^{ihb193/ihb193}	standard conditions	Day 4	liver	ISH	Fig. 4
ccnd1	nr5a2^{ihb193/ihb193}	standard conditions	Day 4	pancreas	ISH	Fig. 4
ccnd1	nr5a2^{ihb195/ihb195}	standard conditions	Day 4	intestine	ISH	Fig. 4
ccnd1	nr5a2^{ihb195/ihb195}	standard conditions	Day 4	liver	ISH	Fig. 4
ccnd1	nr5a2^{ihb195/ihb195}	standard conditions	Day 4	pancreas	ISH	Fig. 4
ccnd1	w32Tg	heat shock	Day 4	intestine	ISH	Fig. 4
ccnd1	w32Tg	control	Day 4	intestine	ISH	Fig. 4
ccnd1	w32Tg	control	Day 4	liver	ISH	Fig. 4
ccnd1	w32Tg	heat shock	Day 4	liver	ISH	Fig. 4

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT	chemical treatment: phosphatidylcholine	Day 4	liver increased size, abnormal	Fig. 6
WT + MO1-nr5a2	standard conditions	Protruding-mouth	intestine decreased size, abnormal	Fig. 2
WT + MO1-nr5a2	standard conditions	Protruding-mouth	liver decreased size, abnormal	Fig. 2
WT + MO1-nr5a2	standard conditions	Protruding-mouth	pancreas decreased size, abnormal	Fig. 2
WT + MO1-pctp	standard conditions	Protruding-mouth	liver decreased size, abnormal	Fig. 6
WT + MO1-pctp	standard conditions	Protruding-mouth	pancreas decreased size, abnormal	Fig. 6
nr5a2^{ihb193/ihb193}	standard conditions	Protruding-mouth	digestive system apoptotic process rate, normal	Fig. 3
nr5a2^{ihb193/ihb193}	standard conditions	Protruding-mouth	digestive system cell population proliferation disrupted, abnormal	Fig. 3
nr5a2^{ihb193/ihb193}	standard conditions	Protruding-mouth	digestive system G1/S transition of mitotic cell cycle delayed, abnormal	Fig. 3
nr5a2^{ihb193/ihb193}	standard conditions	Day 4	digestion decreased rate, abnormal	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
gz15Tg	Tg(ela3l:EGFP) Tg(fabp10a:DsRed)	Transgenic Insertion
ihb193		Indel	nr5a2
ihb195		Small Deletion	nr5a2
w32Tg	Tg(hsp70l:dkk1b-GFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
nr5a2	MO1-nr5a2	MRPHLNO
nr5a2	TALEN2-nr5a2	TALEN
pctp	MO1-pctp	MRPHLNO

Fish

Fish
gz15Tg
nr5a2^{ihb193/ihb193}
nr5a2^{ihb193/ihb193}; gz15Tg
nr5a2^{ihb195/ihb195}
w32Tg
WT
WT + MO1-nr5a2
WT + MO1-pctp

Antibodies

Orthology

Engineered Foreign Genes

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

Mapping

Zhai et al., 2017 ZDB-PUB-170624-12 PMID:28642062

LRH-1 senses signaling from phosphatidylcholine to regulate the expansion growth of digestive organs via synergy with Wnt/β-catenin signaling in zebrafish

Zhai et al., 2017

ZDB-PUB-170624-12
PMID:28642062