PUBLICATION

APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development

Authors

Goessling, W., North, T.E., Lord, A.M., Ceol, C., Lee, S., Weidinger, G., Bourque, C., Strijbosch, R., Haramis, A.P., Puder, M., Clevers, H., Moon, R.T., and Zon, L.I.

ID

ZDB-PUB-080701-3

Date

2008

Source

Developmental Biology 320(1): 161-174 (Journal)

Registered Authors

Bourque, Caitlin, Ceol, Craig, Clevers, Hans, Goessling, Wolfram, Haramis, Anna-Pavlina, Lord, Allegra, Moon, Randall T., North, Trista, Weidinger, Gilbert, Zon, Leonard I.

Keywords

wnt, Endoderm, Liver, Regeneration, APC, Zebrafish, β-catenin

MeSH Terms

beta Catenin/metabolism
Endoderm/cytology
Endoderm/embryology
Hepatectomy
Cell Proliferation
Wnt Proteins/metabolism*
Mutation/genetics*
Apoptosis
Adenomatous Polyposis Coli Protein/metabolism*
Embryo, Nonmammalian/embryology
Embryo, Nonmammalian/metabolism
Animals
Body Patterning
Stem Cells/cytology
Cell Lineage
Phenotype
Time Factors
Zebrafish/embryology*
Liver Regeneration
Hepatocytes/cytology
Liver/cytology
Liver/embryology*
Signal Transduction*

(all 23)

PubMed

18585699 Full text @ Dev. Biol.

Abstract

Developmental signaling pathways hold the keys to unlocking the promise of adult tissue regeneration, and to inhibiting carcinogenesis. Patients with mutations in the Adenomatous Polyposis Coli (APC) gene are at increased risk of developing hepatoblastoma, an embryonal form of liver cancer, suggesting that Wnt affects hepatic progenitor cells. To elucidate the role of APC loss and enhanced Wnt activity in liver development, we examined APC mutant and wnt inducible transgenic zebrafish. APC(+/-) embryos developed enlarged livers through biased induction of hepatic gene programs and increased proliferation. Conversely, APC(-/-) embryos formed no livers. Blastula transplantations determined that the effects of APC loss were cell autonomous. Induction of wnt modulators confirmed biphasic consequences of wnt activation: endodermal pattern formation and gene expression required suppression of wnt signaling in early somitogenesis; later, increased wnt activity altered endodermal fate by enhancing liver growth at the expense of pancreas formation; these effects persisted into the larval stage. In adult APC(+/-) zebrafish, increased wnt activity significantly accelerated liver regeneration after partial hepatectomy. Similarly, liver regeneration was significantly enhanced in APC(Min/+) mice, indicating the conserved effect of Wnt pathway activation in liver regeneration across vertebrate species. These studies reveal an important and time-dependent role for wnt signaling during liver development and regeneration.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
ccnd1	w34Tg	heat shock	Long-pec		whole organism	RTPCR	Fig. 5
ccnd1	w34Tg	heat shock	Long-pec		whole organism	RTPCR	Fig. 5
ccnd1	WT	control	Long-pec		whole organism	RTPCR	Fig. 5
DsRed	apc^hu745/+; zf129Tg	standard conditions	Day 6		intestine	IFL	Fig. S6
DsRed	zf129Tg	standard conditions	Day 6		intestine	IFL	Fig. S6
EGFP	apc^hu745/hu745; as3Tg	standard conditions	Protruding-mouth	Not Detected	liver	IFL	Fig. 1
EGFP	apc^hu745/+; as3Tg	standard conditions	Day 6		liver	IFL	Fig. S6
EGFP	apc^hu745/+; as3Tg	standard conditions	Protruding-mouth		liver	IFL	Fig. 1
EGFP	apc^hu745/+; jh1Tg	standard conditions	Day 6		pancreas	IFL	Fig. S6
EGFP	as3Tg	standard conditions	Protruding-mouth		liver	IFL	Fig. 1

1 - 10 of 100

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
apc^hu745/+	control	Protruding-mouth	liver increased size, abnormal	Fig. 2
apc^hu745/+	standard conditions	Prim-5	endoderm development disrupted, abnormal	Fig. 4
apc^hu745/+	standard conditions	Prim-5	endoderm development disrupted, abnormal	Fig. S3
apc^hu745/+	standard conditions	Prim-5	liver primordium increased size, abnormal	Fig. 4
apc^hu745/+	standard conditions	Prim-5	liver primordium increased size, abnormal	Fig. S3
apc^hu745/+	standard conditions	Prim-5	pancreatic bud decreased size, abnormal	Fig. 4
apc^hu745/+	standard conditions	Prim-5	pancreatic bud decreased size, abnormal	Fig. S3
apc^hu745/+	standard conditions	Long-pec	endoderm development disrupted, abnormal	Fig. 4
apc^hu745/+	standard conditions	Long-pec	liver increased size, abnormal	Fig. 4
apc^hu745/+	standard conditions	Long-pec	pancreas decreased size, abnormal	Fig. 4

1 - 10 of 39

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
as3Tg	Tg(-2.8fabp10a:EGFP)	Transgenic Insertion
hu745		Point Mutation	apc
jh1Tg	Tg(ptf1a:EGFP)	Transgenic Insertion
s854Tg	Tg(Xla.Eef1a1:GFP)	Transgenic Insertion
w26Tg	Tg(hsp70l:tcf7l1a-GFP)	Transgenic Insertion
w32Tg	Tg(hsp70l:dkk1b-GFP)	Transgenic Insertion
w34Tg	Tg(hsp70l:wnt8a-GFP)	Transgenic Insertion
zf129Tg	Tg(fabp2:DsRed)	Transgenic Insertion

1 - 8 of 8

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
ctnnb1	MO1-ctnnb1	MRPHLNO

Fish

Fish
apc^hu745/hu745
apc^hu745/hu745; as3Tg
apc^hu745/hu745 + MO1-ctnnb1
apc^hu745/hu745; s854Tg
apc^hu745/+
apc^hu745/+; as3Tg
apc^hu745/+; jh1Tg
apc^hu745/+ + MO1-ctnnb1
apc^hu745/+; s854Tg
apc^hu745/+; zf129Tg

1 - 10 of 19

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab2-ctnnb	monoclonal	ctnnb1	IgG1	Mouse
Ab3-BrdU	monoclonal		IgG1	Mouse

Orthology

Engineered Foreign Genes

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

Mapping

Goessling et al., 2008 ZDB-PUB-080701-3 PMID:18585699

APC mutant zebrafish uncover a changing temporal requirement for wnt signaling in liver development

Goessling et al., 2008

ZDB-PUB-080701-3
PMID:18585699