PUBLICATION

Developmentally regulated Tcf7l2 splice variants mediate transcriptional repressor functions during eye formation

Authors

Young, R.M., Ewan, K.B., Ferrer, V.P., Allende, M.L., Godovac-Zimmermann, J., Dale, T.C., Wilson, S.W.

ID

ZDB-PUB-191213-10

Date

2019

Source

eLIFE 8: (Journal)

Registered Authors

Allende, Miguel L., Ferrer, Veronica, Young, Rodrigo

Keywords

alternative splicing, developmental biology, eye development, tcf7l2, zebrafish

MeSH Terms

Gene Expression Regulation, Developmental*
Humans
HEK293 Cells
Zebrafish
Animals
Transcription Factor 7-Like 2 Protein/biosynthesis*
Transcription Factor 7-Like 2 Protein/genetics
Transcription Factor 7-Like 2 Protein/metabolism
RNA Splicing*
Protein Isoforms/biosynthesis*
Protein Isoforms/genetics
Transcription, Genetic*
Wnt Signaling Pathway
Eye/embryology*
Zebrafish Proteins/biosynthesis*
Zebrafish Proteins/genetics

(all 16)

PubMed

31829936 Full text @ Elife

Abstract

Tcf7l2 mediates Wnt/β-Catenin signalling during development and is implicated in cancer and type-2 diabetes. The mechanisms by which Tcf7l2 and Wnt/β-Catenin signalling elicit such a diversity of biological outcomes are poorly understood. Here, we study the function of zebrafish tcf7l2alternative splice variants and show that only variants that include exon five or an analogous human tcf7l2 variant can effectively provide compensatory repressor function to restore eye formation in embryos lacking tcf7l1a/tcf7l1b function. Knockdown of exon five specific tcf7l2 variants in tcf7l1a mutants also compromises eye formation, and these variants can effectively repress Wnt pathway activity in reporter assays using Wnt target gene promoters. We show that the repressive activities of exon5-coded variants are likely explained by their interaction with Tle co-repressors. Furthermore, phosphorylated residues in Tcf7l2 coded exon5 facilitate repressor activity. Our studies suggest that developmentally regulated splicing of tcf7l2 can influence the transcriptional output of the Wnt pathway.

Genes / Markers

Figures

Show all Figures

Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
tcf7l2	WT	standard conditions	Adult	brain	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Adult	eye	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Bud	forebrain neural plate	ISH	Figure 1
tcf7l2	WT	standard conditions	Adult	gut	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Adult	liver	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Bud	midbrain neural plate	ISH	Figure 1
tcf7l2	WT	standard conditions	Adult	ovary	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Adult	pancreas	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Adult	testis	RTPCR	Figure 2.
tcf7l2	WT	standard conditions	Day 4	whole organism	RTPCR	Figure 2.

1 - 10 of 16

Show

Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO7-tcf7l2	standard conditions	Prim-15	eye decreased size, abnormal	Figure 3—figure supplement 2.
tcf7l1a^m881/m881	standard conditions	Prim-5 to Prim-15	eye decreased size, abnormal	Figure 3.
tcf7l1a^m881/m881 + MO5-tcf7l1b	standard conditions	Prim-5 to Prim-15	eye absent, abnormal	Figure 3.
tcf7l1a^m881/m881 + MO7-tcf7l2	standard conditions	Prim-5 to Prim-15	eye absent, abnormal	Figure 3.
tcf7l1a^m881/m881; tcf7l2^zf55/zf55	standard conditions	Prim-5 to Prim-15	eye decreased size, exacerbated	Figure 3.
tcf7l2^zf55/zf55	standard conditions	Prim-5 to Prim-15	eye size, normal	Figure 3.

1 - 6 of 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
m881		Point Mutation	tcf7l1a
zf55		Point Mutation	tcf7l2
zf157Tg	Tg(ZM)	Transgenic Insertion	tcf7l1b

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
tcf7l1b	MO5-tcf7l1b	MRPHLNO
tcf7l2	MO6-tcf7l2	MRPHLNO
tcf7l2	MO7-tcf7l2	MRPHLNO

Fish

Fish
tcf7l1a^m881/m881
tcf7l1a^m881/m881 + MO5-tcf7l1b
tcf7l1a^m881/m881 + MO7-tcf7l2
tcf7l1a^m881/m881; tcf7l2^zf55/zf55
tcf7l2^zf55/zf55
WT
WT + MO7-tcf7l2

Antibodies

Orthology

Engineered Foreign Genes

Mapping

Young et al., 2019 ZDB-PUB-191213-10 PMID:31829936

Developmentally regulated Tcf7l2 splice variants mediate transcriptional repressor functions during eye formation

Young et al., 2019

ZDB-PUB-191213-10
PMID:31829936