In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation

Zhiyong Liu, Thomas Owen, Jie Fang, R. Sathish Srinivasan, Jian Zuo

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

Background: Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs). Overactivation of the Notch1 intracellular domain (NICD) in progenitors blocks HC fate commitment and/or differentiation. However, it is not known whether reactivation of NICD in differentiating HCs also interrupts their developmental program and reactivates its downstream targets.

Results: By analyzing Atoh1 CreER+; Rosa26-NICD loxp/+ or Atoh1 CreER+; Rosa26-NICD loxp/+; RBP-J loxp/loxp mice, we demonstrated that ectopic NICD in differentiating HCs caused reactivation of Sox2 and Prox1 in an RBP-J-dependent manner. Interestingly, Prox1 reactivation was exclusive to outer HCs (OHCs). In addition, lineage tracing analysis of Prox1 CreER/+; Rosa26-EYFP loxp/+ and Prox1 CreEGFP/+; Rosa26-EYFP loxp/+ mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology, and uptake of FM4-64FX dye at adult ages.

Conclusions: Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.

Original languageEnglish
Pages (from-to)684-696
JournalDevelopmental Dynamics
Volume241
Issue number4
DOIs
Publication statusPublished - Apr 2012

Fingerprint

Auditory Hair Cells
Hair
Cochlea
Outer Auditory Hair Cells
Cell Differentiation
Coloring Agents

Keywords

  • hair cells
  • cochlea
  • Sox2
  • differentiation
  • Prox1
  • notch

Cite this

In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation. / Liu, Zhiyong; Owen, Thomas; Fang, Jie; Srinivasan, R. Sathish; Zuo, Jian.

In: Developmental Dynamics, Vol. 241, No. 4, 04.2012, p. 684-696.

Research output: Contribution to journalArticle

Liu, Zhiyong ; Owen, Thomas ; Fang, Jie ; Srinivasan, R. Sathish ; Zuo, Jian. / In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation. In: Developmental Dynamics. 2012 ; Vol. 241, No. 4. pp. 684-696.
@article{6cd5cbff9b994c34aa68403105a20f8f,
title = "In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation",
abstract = "Background: Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs). Overactivation of the Notch1 intracellular domain (NICD) in progenitors blocks HC fate commitment and/or differentiation. However, it is not known whether reactivation of NICD in differentiating HCs also interrupts their developmental program and reactivates its downstream targets. Results: By analyzing Atoh1 CreER+; Rosa26-NICD loxp/+ or Atoh1 CreER+; Rosa26-NICD loxp/+; RBP-J loxp/loxp mice, we demonstrated that ectopic NICD in differentiating HCs caused reactivation of Sox2 and Prox1 in an RBP-J-dependent manner. Interestingly, Prox1 reactivation was exclusive to outer HCs (OHCs). In addition, lineage tracing analysis of Prox1 CreER/+; Rosa26-EYFP loxp/+ and Prox1 CreEGFP/+; Rosa26-EYFP loxp/+ mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology, and uptake of FM4-64FX dye at adult ages. Conclusions: Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.",
keywords = "hair cells, cochlea, Sox2, differentiation, Prox1, notch",
author = "Zhiyong Liu and Thomas Owen and Jie Fang and Srinivasan, {R. Sathish} and Jian Zuo",
year = "2012",
month = "4",
doi = "10.1002/dvdy.23754",
language = "English",
volume = "241",
pages = "684--696",
journal = "Developmental Dynamics",
issn = "1058-8388",
publisher = "Wiley-Liss Inc.",
number = "4",

}

TY - JOUR

T1 - In vivo notch reactivation in differentiating cochlear hair cells induces sox2 and prox1 expression but does not disrupt hair cell maturation

AU - Liu, Zhiyong

AU - Owen, Thomas

AU - Fang, Jie

AU - Srinivasan, R. Sathish

AU - Zuo, Jian

PY - 2012/4

Y1 - 2012/4

N2 - Background: Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs). Overactivation of the Notch1 intracellular domain (NICD) in progenitors blocks HC fate commitment and/or differentiation. However, it is not known whether reactivation of NICD in differentiating HCs also interrupts their developmental program and reactivates its downstream targets. Results: By analyzing Atoh1 CreER+; Rosa26-NICD loxp/+ or Atoh1 CreER+; Rosa26-NICD loxp/+; RBP-J loxp/loxp mice, we demonstrated that ectopic NICD in differentiating HCs caused reactivation of Sox2 and Prox1 in an RBP-J-dependent manner. Interestingly, Prox1 reactivation was exclusive to outer HCs (OHCs). In addition, lineage tracing analysis of Prox1 CreER/+; Rosa26-EYFP loxp/+ and Prox1 CreEGFP/+; Rosa26-EYFP loxp/+ mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology, and uptake of FM4-64FX dye at adult ages. Conclusions: Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.

AB - Background: Notch signaling is active in mouse cochlear prosensory progenitors but declines in differentiating sensory hair cells (HCs). Overactivation of the Notch1 intracellular domain (NICD) in progenitors blocks HC fate commitment and/or differentiation. However, it is not known whether reactivation of NICD in differentiating HCs also interrupts their developmental program and reactivates its downstream targets. Results: By analyzing Atoh1 CreER+; Rosa26-NICD loxp/+ or Atoh1 CreER+; Rosa26-NICD loxp/+; RBP-J loxp/loxp mice, we demonstrated that ectopic NICD in differentiating HCs caused reactivation of Sox2 and Prox1 in an RBP-J-dependent manner. Interestingly, Prox1 reactivation was exclusive to outer HCs (OHCs). In addition, lineage tracing analysis of Prox1 CreER/+; Rosa26-EYFP loxp/+ and Prox1 CreEGFP/+; Rosa26-EYFP loxp/+ mice showed that nearly all HCs experiencing Prox1 expression were OHCs. Surprisingly, these HCs still matured normally with expression of prestin, wild-type-like morphology, and uptake of FM4-64FX dye at adult ages. Conclusions: Our results suggest that the developmental program of cochlear differentiating HCs is refractory to Notch reactivation and that Notch is an upstream regulator of Sox2 and Prox1 in cochlear development. In addition, our results support that Sox2 and Prox1 should not be the main blockers for terminal differentiation of HCs newly regenerated from postnatal cochlear SCs that still maintain Sox2 and Prox1 expression.

KW - hair cells

KW - cochlea

KW - Sox2

KW - differentiation

KW - Prox1

KW - notch

UR - http://www.scopus.com/inward/record.url?scp=84862777635&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1002/dvdy.23754

U2 - 10.1002/dvdy.23754

DO - 10.1002/dvdy.23754

M3 - Article

VL - 241

SP - 684

EP - 696

JO - Developmental Dynamics

JF - Developmental Dynamics

SN - 1058-8388

IS - 4

ER -