PUBLICATION

Distinct Wnt signaling pathways have opposing roles in appendage regeneration

Authors

Stoick-Cooper, C.L., Weidinger, G., Riehle, K.J., Hubbert, C., Major, M.B., Fausto N., and Moon, R.T.

ID

ZDB-PUB-061229-24

Date

2007

Source

Development (Cambridge, England) 134(3): 479-489 (Journal)

Registered Authors

Moon, Randall T., Weidinger, Gilbert

Keywords

Wnt, zebrafish, regeneration, β-catenin, dickkopf, wnt8, wnt5, pipetail, axin1, masterblind

MeSH Terms

Feedback
Regeneration/genetics
Regeneration/physiology*
Zebrafish/genetics
Zebrafish/physiology*
Tail
Adult Stem Cells/cytology
Adult Stem Cells/physiology
DNA Primers/genetics
Wnt Proteins/genetics
Wnt Proteins/physiology*
Base Sequence
beta Catenin/genetics
beta Catenin/physiology
Signal Transduction
Animals, Genetically Modified
Animals
Zebrafish Proteins/genetics
Zebrafish Proteins/physiology*

(all 19)

PubMed

17185322 Full text @ Development

Abstract

In contrast to mammals, lower vertebrates have a remarkable capacity to regenerate complex structures damaged by injury or disease. This process, termed epimorphic regeneration, involves progenitor cells created through the reprogramming of differentiated cells or through the activation of resident stem cells. Wnt/beta-catenin signaling regulates progenitor cell fate and proliferation during embryonic development and stem cell function in adults, but its functional involvement in epimorphic regeneration has not been addressed. Using transgenic fish lines, we show that Wnt/beta-catenin signaling is activated in the regenerating zebrafish tail fin and is required for formation and subsequent proliferation of the progenitor cells of the blastema. Wnt/beta-catenin signaling appears to act upstream of FGF signaling, which has recently been found to be essential for fin regeneration. Intriguingly, increased Wnt/beta-catenin signaling is sufficient to augment regeneration, as tail fins regenerate faster in fish heterozygous for a loss-of-function mutation in axin1, a negative regulator of the pathway. Likewise, activation of Wnt/beta-catenin signaling by overexpression of wnt8 increases proliferation of progenitor cells in the regenerating fin. By contrast, overexpression of wnt5b (pipetail) reduces expression of Wnt/beta-catenin target genes, impairs proliferation of progenitors and inhibits fin regeneration. Importantly, fin regeneration is accelerated in wnt5b mutant fish. These data suggest that Wnt/beta-catenin signaling promotes regeneration, whereas a distinct pathway activated by wnt5b acts in a negative-feedback loop to limit regeneration.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
axin2	w33Tg/+	physical alteration: anatomical structure, heat shock	Adult	Not Detected	regenerating fin	ISH	Fig. 4
axin2	w34Tg/+	physical alteration: anatomical structure, heat shock	Adult		regenerating fin	ISH	Fig. 4
axin2	WT	physical alteration: anatomical structure	Adult		blastema	ISH	Fig. 1
axin2	WT	standard conditions	Adult	Not Detected	caudal fin	ISH	Fig. 1
axin2	WT	physical alteration: anatomical structure, heat shock	Adult		regenerating fin	ISH	Fig. 4
axin2	WT	physical alteration: anatomical structure	Adult		regenerating fin	ISH	Fig. 1
fgf20a	w32Tg/+	physical alteration: anatomical structure, heat shock	Adult		regenerating fin	ISH	Fig. 7
fgf20a	w32Tg/+	physical alteration: anatomical structure, heat shock	Adult		regenerating fin	RTPCR	Fig. 7
fgf20a	WT	physical alteration: anatomical structure, heat shock	Adult		regenerating fin	ISH	Fig. 7
fgf20a	WT	physical alteration: anatomical structure, heat shock	Adult		regenerating fin	RTPCR	Fig. 7

1 - 10 of 39

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
axin1^tm13/+	physical alteration: anatomical structure, heat shock	Adult	fin regeneration increased rate, abnormal	Fig. 5
w26Tg	physical alteration: anatomical structure, heat shock	Adult	fin regeneration disrupted, abnormal	Fig. 2
w26Tg	physical alteration: anatomical structure, heat shock	Adult	regenerating fin decreased length, abnormal	Fig. 2
w32Tg/+	standard conditions	Prim-5	anterior/posterior pattern specification disrupted, abnormal	Fig. S3
w32Tg/+	physical alteration: anatomical structure, heat shock	Adult	blastema aplastic, abnormal	Fig. 2
w32Tg/+	physical alteration: anatomical structure, heat shock	Adult	blastema cellular quality, abnormal	Fig. 3
w32Tg/+	physical alteration: anatomical structure, heat shock	Adult	blastema hypoplastic, abnormal	Fig. 3
w32Tg/+	physical alteration: anatomical structure, heat shock	Adult	blastemal cell decreased amount, abnormal	Fig. 3
w32Tg/+	physical alteration: anatomical structure, heat shock	Adult	cell population proliferation decreased rate, abnormal	Fig. 3
w32Tg/+	physical alteration: anatomical structure, heat shock	Adult	fin regeneration disrupted, abnormal	Fig. 2

1 - 10 of 20

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ta98		Point Mutation	wnt5b
tm13		Point Mutation	axin1
w25Tg	Tg(top:GFP)	Transgenic Insertion
w26Tg	Tg(hsp70l:tcf7l1a-GFP)	Transgenic Insertion
w32Tg	Tg(hsp70l:dkk1b-GFP)	Transgenic Insertion
w33Tg	Tg(hsp70l:wnt5b-GFP)	Transgenic Insertion
w34Tg	Tg(hsp70l:wnt8a-GFP)	Transgenic Insertion

1 - 7 of 7

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
axin1^tm13/+
w25Tg
w26Tg
w32Tg/+
w33Tg/+
w34Tg/+
wnt5b^ta98/ta98
WT

Antibodies

Orthology

Gene	Orthology
wnt5a
wnt5b

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Stoick-Cooper et al., 2007 ZDB-PUB-061229-24 PMID:17185322

Distinct Wnt signaling pathways have opposing roles in appendage regeneration

Stoick-Cooper et al., 2007

ZDB-PUB-061229-24
PMID:17185322