Document Detail


Overactivation of Notch1 signaling induces ectopic hair cells in the mouse inner ear in an age-dependent manner.
MedLine Citation:
PMID:  22448289     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: During mouse inner ear development, Notch1 signaling first specifies sensory progenitors, and subsequently controls progenitors to further differentiate into either hair cells (HCs) or supporting cells (SCs). Overactivation of NICD (Notch1 intracellular domain) at early embryonic stages leads to ectopic HC formation. However, it remains unclear whether such an effect can be elicited at later embryonic or postnatal stages, which has important implications in mouse HC regeneration by reactivation of Notch1 signaling.
METHODOLOGY/PRINCIPAL FINDINGS: We performed comprehensive in vivo inducible overactivation of NICD at various developmental stages. In CAG(CreER+); Rosa26-NICD(loxp/+) mice, tamoxifen treatment at embryonic day 10.5 (E10.5) generated ectopic HCs in the non-sensory regions in both utricle and cochlea, whereas ectopic HCs only appeared in the utricle when tamoxifen was given at E13. When tamoxifen was injected at postnatal day 0 (P0) and P1, no ectopic HCs were observed in either utricle or cochlea. Interestingly, Notch1 signaling induced new HCs in a non-cell-autonomous manner, because the new HCs did not express NICD. Adjacent to the new HCs were cells expressing the SC marker Sox10 (either NICD+ or NICD-negative).
CONCLUSIONS/SIGNIFICANCE: Our data demonstrate that the developmental stage determines responsiveness of embryonic otic precursors and neonatal non-sensory epithelial cells to NICD overactivation, and that Notch 1 signaling in the wild type, postnatal inner ear is not sufficient for generating new HCs. Thus, our genetic mouse model is suitable to test additional pathways that could synergistically interact with Notch1 pathway to produce HCs at postnatal ages.
Authors:
Zhiyong Liu; Thomas Owen; Jie Fang; Jian Zuo
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-03-20
Journal Detail:
Title:  PloS one     Volume:  7     ISSN:  1932-6203     ISO Abbreviation:  PLoS ONE     Publication Date:  2012  
Date Detail:
Created Date:  2012-03-26     Completed Date:  2012-08-20     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  101285081     Medline TA:  PLoS One     Country:  United States    
Other Details:
Languages:  eng     Pagination:  e34123     Citation Subset:  IM    
Affiliation:
Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
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MeSH Terms
Descriptor/Qualifier:
Age Factors
Animals
Animals, Newborn
Cell Communication
Cochlea / metabolism,  pathology*
Ear, Inner / cytology*,  embryology,  metabolism
Female
Fluorescent Antibody Technique
Hair Cells, Auditory / cytology*,  metabolism
Male
Mice
Mice, Knockout
Mice, Transgenic
Proteins / physiology
Receptors, Notch / physiology*
Regeneration / physiology*
Signal Transduction*
Grant Support
ID/Acronym/Agency:
CA21765/CA/NCI NIH HHS; DC008800/DC/NIDCD NIH HHS; DC05168/DC/NIDCD NIH HHS; DC06471/DC/NIDCD NIH HHS
Chemical
Reg. No./Substance:
0/Gt(ROSA)26Sor protein, mouse; 0/Proteins; 0/Receptors, Notch
Comments/Corrections

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