PUBLICATION

Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration

Authors

Lee, S.G., Huang, M., Obholzer, N.D., Sun, S., Li, W., Petrillo, M., Dai, P., Zhou, Y., Cotanche, D.A., Megason, S.G., Li, H., Chen, Z.Y.

ID

ZDB-PUB-160630-14

Date

2016

Source

PLoS One 11: e0157768 (Journal)

Registered Authors

Megason, Sean, Obholzer, Nikolaus, Zhou, Yi

Keywords

Zebrafish, Neomycins, Larvae, In situ hybridization, Cell cycle and cell division, Microarrays, Inner ear, Gene expression

MeSH Terms

Animals
Zebrafish
Regeneration*
Proto-Oncogene Proteins c-myc/genetics
Proto-Oncogene Proteins c-myc/metabolism*
Receptors, Fibroblast Growth Factor/genetics
Receptors, Fibroblast Growth Factor/metabolism
Mast Cells/cytology
Mast Cells/metabolism*
Mast Cells/physiology
Fibroblast Growth Factors/genetics
Fibroblast Growth Factors/metabolism*
Neurons, Afferent/cytology
Neurons, Afferent/metabolism*
Neurons, Afferent/physiology
Lateral Line System/cytology
Lateral Line System/metabolism*
Lateral Line System/physiology
Zebrafish Proteins/genetics
Zebrafish Proteins/metabolism
Cell Proliferation

(all 21)

PubMed

27351484 Full text @ PLoS One

Abstract

Unlike mammals, the non-mammalian vertebrate inner ear can regenerate the sensory cells, hair cells, either spontaneously or through induction after hair cell loss, leading to hearing recovery. The mechanisms underlying the regeneration are poorly understood. By microarray analysis on a chick model, we show that chick hair cell regeneration involves the activation of proliferation genes and downregulation of differentiation genes. Both MYC and FGF are activated in chick hair cell regeneration. Using a zebrafish lateral line neuromast hair cell regeneration model, we show that the specific inhibition of Myc or Fgf suppresses hair cell regeneration, demonstrating that both pathways are essential to the process. Rapid upregulation of Myc and delayed Fgf activation during regeneration suggest a role of Myc in proliferation and Fgf in differentiation. The dorsal-ventral pattern of fgfr1a in the neuromasts overlaps with the distribution of hair cell precursors. By laser ablation, we show that the fgfr1a-positive supporting cells are likely the hair cell precursors that directly give rise to new hair cells; whereas the anterior-posterior fgfr1a-negative supporting cells have heightened proliferation capacity, likely to serve as more primitive progenitor cells to replenish lost precursors after hair cell loss. Thus fgfr1a is likely to mark compartmentalized supporting cell subtypes with different capacities in renewal proliferation and hair cell regeneration. Manipulation of c-MYC and FGF pathways could be explored for mammalian hair cell regeneration.

Genes / Markers

Figures

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Expression

Gene	Fish	Conditions	Stage	Anatomy	Assay	Figure
atoh1a	AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast	ISH	Fig. 3
atoh1a	AB	control	Day 5	neuromast	ISH	Fig. 3
etv4	AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 6	neuromast	IHC	Fig. 4
etv4	AB	standard conditions	Day 6	neuromast	IHC	Fig. 4
etv4	AB	chemical treatment by environment: neomycin, chemical treatment: SU5402	Day 6	neuromast	IHC	Fig. 4
fgf10a	AB	control	Day 5	neuromast hair cell	ISH	Fig. 1
fgf10a	AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 6	neuromast hair cell	ISH	Fig. 1
fgf10a	AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast hair cell	ISH	Fig. 1
fgf3	AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 6	neuromast hair cell	ISH	Fig. 1
fgf3	AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast hair cell	ISH	Fig. 1

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Phenotype

Fish	Conditions	Stage	Phenotype	Figure
AB	chemical treatment by environment: neomycin, chemical treatment: thiazolidinone	Days 7-13	neuromast hair cell decreased amount, abnormal	Fig. 2
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast atoh1a expression increased amount, abnormal	Fig. 3
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast Ab6-vim labeling decreased amount, abnormal	Fig. 3
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast hair cell fgf10a expression decreased amount, abnormal	Fig. 1
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast hair cell fgf3 expression decreased amount, abnormal	Fig. 1
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast support cell fgfr1a expression decreased amount, abnormal	Fig. 1
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast support cell fgfr2 expression decreased amount, abnormal	Fig. 1
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast support cell mycb expression increased amount, abnormal	Fig. 1
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 5	neuromast support cell odc1 expression increased amount, abnormal	Fig. 2
AB	chemical treatment by environment: neomycin, chemical ablation: neuromast hair cell	Day 6	neuromast etv4 expression increased amount, abnormal	Fig. 4

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Mutations / Transgenics

Allele	Construct	Type	Affected Genomic Region
b4		Insertion	slc45a2
pd1Tg	Tg(hsp70l:dnfgfr1a-EGFP)	Transgenic Insertion
s356tTg	Tg(pou4f3:GAP-GFP)	Transgenic Insertion
sqet20Et	Et(krt4:EGFP)	Transgenic Insertion

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Human Disease / Model

Sequence Targeting Reagents

Fish

Fish
AB
pd1Tg
s356tTg; sqet20Et

Antibodies

Name	Type	Antigen Genes	Isotypes	Host Organism
Ab1-otof	monoclonal	otofa otofb	IgG2a	Mouse
Ab6-vim	monoclonal		IgM	Mouse

Orthology

Engineered Foreign Genes

Marker	Marker Type	Name
EGFP	EFG	EGFP
GFP	EFG	GFP

Mapping

Lee et al., 2016 ZDB-PUB-160630-14 PMID:27351484

Myc and Fgf Are Required for Zebrafish Neuromast Hair Cell Regeneration

Lee et al., 2016

ZDB-PUB-160630-14
PMID:27351484