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PMID:25535395

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Citation

Li, W, Wu, J, Yang, J, Sun, S, Chai, R, Chen, ZY and Li, H (2015) Notch inhibition induces mitotically generated hair cells in mammalian cochleae via activating the Wnt pathway. Proc. Natl. Acad. Sci. U.S.A. 112:166-71

Abstract

The activation of cochlear progenitor cells is a promising approach for hair cell (HC) regeneration and hearing recovery. The mechanisms underlying the initiation of proliferation of postnatal cochlear progenitor cells and their transdifferentiation to HCs remain to be determined. We show that Notch inhibition initiates proliferation of supporting cells (SCs) and mitotic regeneration of HCs in neonatal mouse cochlea in vivo and in vitro. Through lineage tracing, we identify that a majority of the proliferating SCs and mitotic-generated HCs induced by Notch inhibition are derived from the Wnt-responsive leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5(+)) progenitor cells. We demonstrate that Notch inhibition removes the brakes on the canonical Wnt signaling and promotes Lgr5(+) progenitor cells to mitotically generate new HCs. Our study reveals a new function of Notch signaling in limiting proliferation and regeneration potential of postnatal cochlear progenitor cells, and provides a new route to regenerate HCs from progenitor cells by interrupting the interaction between the Notch and Wnt pathways.

Links

PubMed PMC4291673 Online version:10.1073/pnas.1415901112

Keywords

Animals; Cell Lineage; Cell Proliferation; Hair Cells, Auditory/cytology; Hair Cells, Auditory/metabolism; Labyrinth Supporting Cells/metabolism; Mice; Mitosis; Receptors, G-Protein-Coupled/metabolism; Receptors, Notch/antagonists & inhibitors; Receptors, Notch/metabolism; SOXB1 Transcription Factors/metabolism; Wnt Signaling Pathway

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:CCND1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HES1

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:CDN1B

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SOX2

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ATOH1

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HES5

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MYO7A

located_in

GO:0005737: cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:NOTC1

acts_upstream_of_or_within

GO:0008285: negative regulation of cell population proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044585

P

Seeded From UniProt

complete

MOUSE:NOTC1

acts_upstream_of_or_within

GO:0006357: regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044585

P

Seeded From UniProt

complete

MOUSE:NOTC1

acts_upstream_of_or_within

GO:0045608: negative regulation of inner ear auditory receptor cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044585

P

Seeded From UniProt

complete

MOUSE:NOTC1

acts_upstream_of_or_within

GO:0045607: regulation of inner ear auditory receptor cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044585

P

Seeded From UniProt

complete

MOUSE:NOTC1

acts_upstream_of_or_within

GO:0042127: regulation of cell population proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1341817

P

Seeded From UniProt

complete

MOUSE:NOTC1

acts_upstream_of_or_within

GO:0090090: negative regulation of canonical Wnt signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:3044585

P

Seeded From UniProt

complete

MOUSE:CTNB1

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SP5

acts_upstream_of_or_within

GO:0071407: cellular response to organic cyclic compound

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:LGR5

acts_upstream_of_or_within

GO:0042127: regulation of cell population proliferation

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:97363

P

Seeded From UniProt

complete

MOUSE:CTNB1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SOX2

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CDN1B

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:CDN1B

acts_upstream_of_or_within

GO:0007219: Notch signaling pathway

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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