PUBLICATION

Convergence of signaling pathways underlying habenular formation and axonal outgrowth

Authors

Roberson, S., Halpern, M.E.

ID

ZDB-PUB-170618-19

Date

2017

Source

Development (Cambridge, England) 144(14): 2652-2662 (Journal)

Registered Authors

Halpern, Marnie E., Roberson, Sara

Keywords

Chemokine, Fgf, Habenula, Interpeduncular nucleus, Shh, Wnt

MeSH Terms

Axons/metabolism
Hedgehog Proteins/genetics
Hedgehog Proteins/metabolism
Wnt Signaling Pathway
Neurogenesis/genetics
Neurogenesis/physiology
Habenula/embryology*
Habenula/metabolism*
Fibroblast Growth Factors/genetics
Fibroblast Growth Factors/metabolism
Homeodomain Proteins/genetics
Homeodomain Proteins/metabolism
Chemokines/genetics
Chemokines/metabolism
Neural Stem Cells/cytology
Neural Stem Cells/metabolism
Signal Transduction
Transcription Factors/genetics
Transcription Factors/metabolism
Receptors, CXCR4/genetics
Receptors, CXCR4/metabolism
Zebrafish/embryology*
Zebrafish/genetics
Zebrafish/metabolism*
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism
Animals
Mutation
Animals, Genetically Modified

(all 29)

PubMed

28619821 Full text @ Development

Abstract

The habenular nuclei are a conserved integrating center in the vertebrate epithalamus, where they modulate diverse behaviors. Despite their importance, our understanding of habenular development is incomplete. Time-lapse imaging and fate mapping demonstrate that the dorsal habenulae (dHb) of zebrafish are derived from dbx1b-expressing (dbx1b⁺ ) progenitors, which transition into cxcr4b-expressing neuronal precursors. The precursors give rise to differentiated neurons, the axons of which innervate the midbrain interpeduncular nucleus (IPN). Formation of the dbx1b⁺ progenitor population relies on the activity of the Shh, Wnt and Fgf signaling pathways. Wnt and Fgf function additively to generate dHb progenitors. Surprisingly, Wnt signaling also negatively regulates fgf8a, confining expression to a discrete dorsal diencephalic domain. Moreover, the Wnt and Fgf pathways have opposing roles in transcriptional regulation of components of the Cxcr4-chemokine signaling pathway. The chemokine pathway, in turn, directs the posterior outgrowth of dHb efferents toward the IPN and, when disrupted, results in ectopic, anteriorly directed axonal projections. The results define a signaling network underlying the generation of dHb neurons and connectivity with their midbrain target.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
ackr3b	fgf8a^{ti282a/ti282a}	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
ackr3b	wls^c186/c186	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
ackr3b	WT	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
ano2b	AB	control	High-pec	dorsal habenular nucleus neuron	ISH	Fig. 3
ano2b	AB	control	Protruding-mouth	dorsal habenular nucleus neuron	ISH	Fig. 3
cxcl12a	nns11Tg	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
cxcl12b	fgf8a^{ti282a/ti282a}	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
cxcl12b	fgf8a^{ti282a/ti282a}; wls^c186/c186	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
cxcl12b	nns11Tg	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6
cxcl12b	wls^c186/c186	control	Prim-15	diencephalon dorsal region	ISH	Fig. 6

1 - 10 of 107

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
cxcr4b^{t26035/t26035}; c375Tg	standard conditions	Day 5	axon guidance disrupted, abnormal	Fig. 7
cxcr4b^{t26035/t26035}; c375Tg	standard conditions	Day 5	dorsal habenular nucleus axon misrouted, abnormal	Fig. 7
cxcr4b^{t26035/t26035}; c375Tg	standard conditions	Day 5	dorsal habenular nucleus neuron projection mislocalised, abnormal	Fig. 7
cxcr4b^{t26035/t26035}; c375Tg	standard conditions	Day 5	dorsal habenular nucleus neuron projection structure, abnormal	Fig. 7
fgf8a^{ti282a/ti282a}	control	Prim-15	diencephalon dorsal region ackr3b expression decreased distribution, abnormal	Fig. 6
fgf8a^{ti282a/ti282a}	control	Prim-15	diencephalon dorsal region cxcl12b expression decreased distribution, abnormal	Fig. 6
fgf8a^{ti282a/ti282a}	control	Prim-15	diencephalon dorsal region dbx1b expression decreased amount, abnormal	Fig. 5
fgf8a^{ti282a/ti282a}; wls^c186/c186	control	Prim-15	diencephalon wls expression absent, abnormal	Fig. 6
fgf8a^{ti282a/ti282a}; wls^c186/c186	control	Prim-15	diencephalon dorsal region cxcl12b expression spatial pattern, ameliorated	Fig. 6
fgf8a^{ti282a/ti282a}; wls^c186/c186	control	Prim-15	diencephalon dorsal region dbx1b expression absent, abnormal	Fig. 5

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
c186		Point Mutation	wls
c375Tg	TgBAC(gng8:Eco.NfsB-2A-CAAX-GFP)	Transgenic Insertion
hi1640Tg	Tg(nLacz-GTvirus)	Transgenic Insertion	smo
jf5Tg	Tg(elavl3:Hsa.H2B-GCaMP6s)	Transgenic Insertion
jh38Tg	Tg(actb2:LOXP-hmgb1a-ECFP-LOXP-zgc:114046-mCherry)	Transgenic Insertion
nns11Tg	TgBAC(dbx1b:GFP)	Transgenic Insertion
nns13aTg	TgBAC(dbx1b:Cre-mCherry)	Transgenic Insertion
nns45Tg	TgBAC(dbx1b:Tomato-NLS)	Transgenic Insertion
sk79Tg	TgBAC(cxcr4b:cxcr4b-mKate2-IRES-EGFP-CAAX,cryaa:DsRed)	Transgenic Insertion
t26035		Point Mutation	cxcr4b

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
c375Tg
c375Tg; jh38Tg; nns13aTg
c375Tg; nns45Tg
cxcr4b^{t26035/t26035}; c375Tg
fgf8a^{ti282a/ti282a}
fgf8a^{ti282a/ti282a}; wls^c186/c186
jf5Tg; zf511Tg
nns11Tg
nns11Tg; zf511Tg

Antibodies

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
Cre	EFG	Cre
DsRed	EFG	DsRed
ECFP	EFG	ECFP
EGFP	EFG	EGFP
GCaMP	EFG	GCaMP
GFP	EFG	GFP
mCherry	EFG	mCherry
mKate2	EFG	mKate2
Tomato	EFG	Tomato

Mapping

Roberson et al., 2017 ZDB-PUB-170618-19 PMID:28619821

Convergence of signaling pathways underlying habenular formation and axonal outgrowth

Roberson et al., 2017

ZDB-PUB-170618-19
PMID:28619821