PUBLICATION

Rest represses maturation within migrating facial branchiomotor neurons

Authors

Love, C.E., Prince, V.E.

ID

ZDB-PUB-150315-2

Date

2015

Source

Developmental Biology 401(2): 220-35 (Journal)

Registered Authors

Love, Crystal, Prince, Victoria E.

Keywords

Facial neurons, Neuronal maturation, Neuronal migration, Prickle1b, Rest, Zebrafish

MeSH Terms

Zebrafish Proteins/genetics
Neurogenesis/genetics*
Motor Neurons/metabolism*
Gene Knockdown Techniques
Zebrafish
Neural Stem Cells/metabolism*
Animals
Nerve Tissue Proteins/genetics
Morpholinos/genetics
Cell Movement/physiology
Repressor Proteins/biosynthesis
Repressor Proteins/genetics*
Rhombencephalon/embryology
Facial Nerve/cytology
Facial Nerve/metabolism*
Cell Nucleus/genetics
Animals, Genetically Modified

(all 17)

PubMed

25769695 Full text @ Dev. Biol.

Abstract

The vertebrate brain arises from the complex organization of millions of neurons. Neurogenesis encompasses not only cell fate specification from neural stem cells, but also the terminal molecular and morphological maturation of neurons at correct positions within the brain. RE1-silencing transcription factor (Rest) is expressed in non-neural tissues and neuronal progenitors where it inhibits the terminal maturation of neurons by repressing hundreds of neuron-specific genes. Here we show that Rest repression of maturation is intimately linked with the migratory capability of zebrafish facial branchiomotor neurons (FBMNs), which undergo a characteristic tangential migration from hindbrain rhombomere (r) 4 to r6/r7 during development. We establish that FBMN migration is increasingly disrupted as Rest is depleted in zebrafish rest mutant embryos, such that around two-thirds of FBMNs fail to complete migration in mutants depleted of both maternal and zygotic Rest. Although Rest is broadly expressed, we show that de-repression or activation of Rest target genes only within FBMNs is sufficient to disrupt their migration. We demonstrate that this migration defect is due to precocious maturation of FBMNs, based on both morphological and molecular criteria. We further show that the Rest target gene and alternative splicing factor srrm4 is a key downstream regulator of maturation; Srrm4 knockdown partially restores the ability of FBMNs to migrate in rest mutants while preventing their precocious morphological maturation. Rest must localize to the nucleus to repress its targets, and its subcellular localization is highly regulated: we show that targeting Rest specifically to FBMN nuclei rescues FBMN migration in Rest-deficient embryos. We conclude that Rest functions in FBMN nuclei to inhibit maturation until the neurons complete their migration.

Genes / Markers

Figures

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Expression

Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
prickle1b^fh122/fh122; rw0Tg	control	Prim-5		facial nerve motor nucleus motor neuron	ISH	Fig. 5
rest^sbu29/sbu29; rw0Tg	control	Prim-5		facial nerve motor nucleus motor neuron	ISH	Fig. 5
rw0Tg	control	Prim-5	Not Detected	facial nerve motor nucleus motor neuron	ISH	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5		facial nerve motor nucleus motor neuron	IHC	Fig. 5
rest^sbu29/sbu29; rw0Tg	control	Prim-5		facial nerve motor nucleus motor neuron	IHC	Fig. 5
rest^sbu29/sbu29; rw0Tg	control	Long-pec		facial nerve motor nucleus motor neuron	IHC	Fig. 3
rest^sbu29/sbu29; rw0Tg	control	Long-pec		facial nerve motor nucleus motor neuron	IHC	Fig. 1
rest^sbu29/sbu29; rw0Tg	control	Protruding-mouth		facial nerve motor nucleus motor neuron	IHC	Fig. 1
rest^sbu29/sbu29; rw0Tg	control	Long-pec		facial nerve motor nucleus motor neuron	IHC	Fig. 1
rest^sbu29/sbu29; rw0Tg	control	Long-pec		facial nerve motor nucleus motor neuron	IHC	Fig. 6

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron adam23a expression increased amount, abnormal	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron met expression increased amount, abnormal	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron snap25b expression increased amount, abnormal	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron srrm4 expression increased amount, abnormal	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron syt4 expression increased amount, abnormal	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron displaced to rhombomere 4, abnormal	Fig. 5
prickle1b^fh122/fh122; rw0Tg	control	Prim-5	facial nerve motor nucleus motor neuron migration arrested, abnormal	Fig. 5
rest^sbu29/+; rw0Tg	control	Long-pec	facial nerve motor nucleus motor neuron displaced to rhombomere 4, abnormal	Fig. 1
rest^sbu29/+; rw0Tg	control	Long-pec	facial nerve motor nucleus motor neuron displaced to rhombomere 4, abnormal	Fig. 1
rest^sbu29/+; rw0Tg	control	Long-pec	facial nerve motor nucleus motor neuron displaced to rhombomere 5, abnormal	Fig. 1

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
ch100Tg	Tg(en.crest1-hsp70l:mRFP)	Transgenic Insertion
fh122		Point Mutation	prickle1b
rw0Tg	Tg(isl1a:GFP)	Transgenic Insertion
sbu29		Small Deletion	rest

1 - 4 of 4

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
rest	MO1-rest	MRPHLNO
rest	MO5-rest	MRPHLNO
srrm4	MO1-srrm4	MRPHLNO

Fish

Fish
ch100Tg
prickle1b^fh122/fh122; rw0Tg
rest^sbu29/sbu29; ch100Tg
rest^sbu29/sbu29; ch100Tg + MO1-srrm4
rest^sbu29/sbu29; rw0Tg
rest^sbu29/sbu29; rw0Tg
rest^sbu29/sbu29; rw0Tg + MO1-srrm4
rest^sbu29/+; rw0Tg
rest^sbu29/+; rw0Tg
rw0Tg

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Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
ab1-epha4a				Rabbit

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
GFP	EFG	GFP
mRFP	EFG	mRFP
RFP	EFG	RFP

Mapping

Love et al., 2015 ZDB-PUB-150315-2 PMID:25769695

Rest represses maturation within migrating facial branchiomotor neurons

Love et al., 2015

ZDB-PUB-150315-2
PMID:25769695