PUBLICATION

Tfap2a Promotes Specification and Maturation of Neurons in the Inner Ear through Modulation of Bmp, Fgf and Notch Signaling

Authors

Kantarci, H., Edlund, R.K., Groves, A.K., Riley, B.B.

ID

ZDB-PUB-150318-1

Date

2015

Source

PLoS Genetics 11: e1005037 (Journal)

Registered Authors

Riley, Bruce

Keywords

Embryos, Vesicles, Neurons, Neuronal differentiation, Neuroblasts, Notch signaling, Neurogenesis, Ears

MeSH Terms

Cell Differentiation/genetics
Chickens
Receptors, Notch/genetics
Receptors, Notch/metabolism
Ear, Inner/growth & development
Ear, Inner/metabolism
Transcription Factor AP-2/biosynthesis*
Transcription Factor AP-2/genetics
Signal Transduction/genetics
Bone Morphogenetic Protein 7/biosynthesis
Bone Morphogenetic Protein 7/genetics*
Gene Expression Regulation, Developmental
Animals
Zebrafish Proteins/biosynthesis*
Zebrafish Proteins/genetics*
Ganglion Cysts/embryology
Ganglion Cysts/genetics*
Zebrafish/genetics
Zebrafish/growth & development
Neurogenesis/genetics*
Fibroblast Growth Factors/genetics
Fibroblast Growth Factors/metabolism

(all 22)

PubMed

25781991 Full text @ PLoS Genet.

Abstract

Neurons of the statoacoustic ganglion (SAG) transmit auditory and vestibular information from the inner ear to the hindbrain. SAG neuroblasts originate in the floor of the otic vesicle. New neuroblasts soon delaminate and migrate towards the hindbrain while continuing to proliferate, a phase known as transit amplification. SAG cells eventually come to rest between the ear and hindbrain before terminally differentiating. Regulation of these events is only partially understood. Fgf initiates neuroblast specification within the ear. Subsequently, Fgf secreted by mature SAG neurons exceeds a maximum threshold, serving to terminate specification and delay maturation of transit-amplifying cells. Notch signaling also limits SAG development, but how it is coordinated with Fgf is unknown. Here we show that transcription factor Tfap2a coordinates multiple signaling pathways to promote neurogenesis in the zebrafish inner ear. In both zebrafish and chick, Tfap2a is expressed in a ventrolateral domain of the otic vesicle that includes neurogenic precursors. Functional studies were conducted in zebrafish. Loss of Tfap2a elevated Fgf and Notch signaling, thereby inhibiting SAG specification and slowing maturation of transit-amplifying cells. Conversely, overexpression of Tfap2a inhibited Fgf and Notch signaling, leading to excess and accelerated SAG production. However, most SAG neurons produced by Tfap2a overexpression died soon after maturation. Directly blocking either Fgf or Notch caused less dramatic acceleration of SAG development without neuronal death, whereas blocking both pathways mimicked all observed effects of Tfap2a overexpression, including apoptosis of mature neurons. Analysis of genetic mosaics showed that Tfap2a acts non-autonomously to inhibit Fgf. This led to the discovery that Tfap2a activates expression of Bmp7a, which in turn inhibits both Fgf and Notch signaling. Blocking Bmp signaling reversed the effects of overexpressing Tfap2a. Together, these data support a model in which Tfap2a, acting through Bmp7a, modulates Fgf and Notch signaling to control the duration, amount and speed of SAG neural development.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Qualifier	Anatomy	Assay	Figure
bmp7a	AB	heat shock	Prim-5		otic vesicle anterior region	ISH	Fig. 9
bmp7a	AB	heat shock	Prim-5		otic vesicle posterior region	ISH	Fig. 9
bmp7a	AB	heat shock	Prim-5		otic vesicle ventro-lateral region	ISH	Fig. 9
bmp7a	tfap2a^m819/m819	standard conditions	Prim-5	Not Detected	otic vesicle anterior region	ISH	Fig. 9
bmp7a	tfap2a^m819/m819	standard conditions	Prim-5		otic vesicle posterior region	ISH	Fig. 9
bmp7a	tfap2a^m819/m819	standard conditions	Prim-5	Not Detected	otic vesicle ventro-lateral region	ISH	Fig. 9
bmp7a	x24Tg	heat shock	Prim-5		otic vesicle anterior region	ISH	Fig. 9
bmp7a	x24Tg	heat shock	Prim-5		otic vesicle posterior region	ISH	Fig. 9
bmp7a	x24Tg	heat shock	Prim-5		otic vesicle ventro-lateral region	ISH	Fig. 9
dla	AB	heat shock	Prim-5		otic vesicle	ISH	Fig. 6

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment: LY-411575	Prim-5	otic vesicle has extra parts of type otic vesicle neuroblast (sensu Vertebrata), abnormal	Fig. 7
AB	chemical treatment: LY-411575	Prim-5	otic vesicle neuroblast fate specification increased occurrence, abnormal	Fig. 7
AB	chemical treatment: LY-411575	Prim-5	otic vesicle Notch signaling pathway decreased process quality, abnormal	Fig. 7
AB	chemical treatment: LY-411575	Prim-25	statoacoustic (VIII) ganglion has fewer parts of type statoacoustic (VIII) ganglion neuroblast (sensu Vertebrata), abnormal	Fig. 7
AB	chemical treatment: LY-411575	Long-pec	statoacoustic (VIII) ganglion has extra parts of type statoacoustic (VIII) ganglion neuron, abnormal	Fig. 7
AB	heat shock	Prim-5	otic vesicle has normal numbers of parts of type otic vesicle neuroblast (sensu Vertebrata), normal	Fig. 2
AB	heat shock	Prim-5	otic vesicle neuroblast fate specification occurrence, normal	Fig. 6
AB	heat shock	Prim-5	otic vesicle neuroblast fate specification occurrence, normal	Fig. 2
AB	heat shock	Prim-15	otic vesicle has normal numbers of parts of type otic vesicle neuroblast (sensu Vertebrata), normal	Fig. 2
AB	heat shock	Prim-15	otic vesicle neuroblast fate specification occurrence, normal	Fig. 2

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
kca3Tg	Tg(5xUAS-E1B:6xMYC-notch1a)	Transgenic Insertion
kca4Tg	Tg(-1.5hsp70l:GAL4)	Transgenic Insertion
m819		Point Mutation	tfap2a
pd1Tg	Tg(hsp70l:dnfgfr1a-EGFP)	Transgenic Insertion
x17Tg	Tg1(hsp70l:fgf8a)	Transgenic Insertion
x24Tg	Tg(hsp70l:tfap2a)	Transgenic Insertion

1 - 6 of 6

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Human Disease / Model

Sequence Targeting Reagents

Target	Reagent	Reagent Type
tfap2a	MO4-tfap2a	MRPHLNO

Fish

Fish
AB
AB + MO4-tfap2a
kca3Tg; kca4Tg
kca3Tg; kca4Tg; x17Tg
pd1Tg
pd1Tg + MO4-tfap2a
tfap2a^m819/m819
x17Tg
x17Tg; x24Tg
x24Tg

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab2-isl	monoclonal	isl1a isl2a	IgG2b	Mouse

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GAL4	EFG	GAL4

Mapping

Kantarci et al., 2015 ZDB-PUB-150318-1 PMID:25781991

Tfap2a Promotes Specification and Maturation of Neurons in the Inner Ear through Modulation of Bmp, Fgf and Notch Signaling

Kantarci et al., 2015

ZDB-PUB-150318-1
PMID:25781991