PUBLICATION

The transcriptional repressor REST/NRSF modulates hedgehog signaling

Authors

Gates, K.P., Mentzer, L., Karlstrom, R.O., and Sirotkin, H.I.

ID

ZDB-PUB-100211-3

Date

2010

Source

Developmental Biology 340(2): 293-305 (Journal)

Registered Authors

Karlstrom, Rolf, Sirotkin, Howard

Keywords

REST/NRSF, Sonic Hedgehog, Transcription factor, Gli, Zebrafish, Neural tube

MeSH Terms

Embryo, Nonmammalian/metabolism
Hedgehog Proteins/genetics
Hedgehog Proteins/metabolism*
Epistasis, Genetic
Signal Transduction/genetics
In Situ Hybridization
Animals
Zebrafish/embryology
Zebrafish/genetics
Zebrafish/metabolism
Repressor Proteins/genetics
Repressor Proteins/metabolism*
Models, Biological
Transcription Factors/antagonists & inhibitors
Transcription Factors/genetics
Transcription Factors/metabolism*

(all 16)

PubMed

20122919 Full text @ Dev. Biol.

Abstract

The spatial and temporal control of gene expression is key to generation of specific cellular fates during development. Studies of the transcriptional repressor REST/NRSF (RE1 Silencing Transcription Factor or Neural Restrictive Silencing Factor) have provided important insight into the role that epigenetic modifications play in differential gene expression. However, the precise function of REST during embryonic development is not well understood. We have discovered a novel interaction between zebrafish Rest and the Hedgehog (Hh) signaling pathway. We observed that Rest knockdown enhances or represses Hh signaling in a context-dependant manner. In wild-type embryos and embryos with elevated Hh signaling, Rest knockdown augments transcription of Hh target genes. Conversely, in contexts where Hh signaling is diminished, Rest knockdown has the opposite effect and Hh target gene expression is further attenuated. Epistatic analysis revealed that Rest interacts with the Hh pathway at a step downstream of Smo. Furthermore, we present evidence implicating the bifunctional, Hh signaling component Gli2a as key to the Rest modulation of the Hh response. The role of Rest as a regulator of Hh signaling has broad implications for many developmental contexts where REST and Hh signaling act.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
dbx1a	WT	control	Prim-5	whole organism	RTPCR	Fig. 2
dbx1a	WT + MO1-rest	standard conditions	Prim-5	whole organism	RTPCR	Fig. 2
foxa2	WT	control	Prim-5	hindbrain neural tube ventral region	ISH	Fig. 2
foxa2	WT	control	Prim-5	pharyngeal endoderm	ISH	Fig. 2
foxa2	WT	control	Prim-5	whole organism	RTPCR	Fig. 2
foxa2	WT + MO1-rest	standard conditions	Prim-5	hindbrain neural tube ventral region	ISH	Fig. 2
foxa2	WT + MO1-rest	standard conditions	Prim-5	pharyngeal endoderm	ISH	Fig. 2
foxa2	WT + MO1-rest	standard conditions	Prim-5	whole organism	RTPCR	Fig. 2
gli1	WT	control	Prim-5	hindbrain neural tube ventral region	ISH	Fig. 6
gli1	WT + MO1-rest	standard conditions	Prim-5	hindbrain neural tube dorsal region	ISH	Fig. 6

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
WT + MO1-rest	standard conditions	Prim-5	dorsal/ventral neural tube patterning disrupted, abnormal	Fig. 2
WT + MO1-rest	standard conditions	Prim-5	neural tube wholly ventralized, abnormal	Fig. 2
WT + MO1-rest	standard conditions	Prim-5	regulation of smoothened signaling pathway disrupted, abnormal	Fig. 2
WT + MO1-rest	standard conditions	Prim-5	smoothened signaling pathway involved in dorsal/ventral neural tube patterning disrupted, abnormal	Fig. 2
WT + MO1-rest	standard conditions	Prim-5 to Protruding-mouth	embryo development decreased rate, abnormal	text only
WT + MO1-rest	standard conditions	Prim-5 to Protruding-mouth	whole organism decreased size, abnormal	text only

1 - 6 of 6

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
rw0Tg	Tg(isl1a:GFP)	Transgenic Insertion
te370a		Point Mutation	gli1
ty17a		Point Mutation	gli2a

Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
gli2a	MO1-gli2a	MRPHLNO
rest	MO1-rest	MRPHLNO
rest	MO2-rest	MRPHLNO

Fish

Fish
gli1^{te370a/te370a}
gli1^{te370a/te370a} + MO1-gli2a
gli1^{te370a/te370a} + MO1-gli2a + MO1-rest
gli1^{te370a/te370a} + MO1-rest
gli2a^ty17a/ty17a
gli2a^ty17a/ty17a + MO1-rest
rw0Tg
WT
WT + MO1-rest
WT + MO2-rest

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Antibodies

Orthology

Gene	Orthology
rest

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP

Mapping

Gates et al., 2010 ZDB-PUB-100211-3 PMID:20122919

The transcriptional repressor REST/NRSF modulates hedgehog signaling

Gates et al., 2010

ZDB-PUB-100211-3
PMID:20122919