The role of her4 in inner ear development and its relationship with proneural genes and Notch signalling

PLoS One. 2014 Oct 9;9(10):e109860. doi: 10.1371/journal.pone.0109860. eCollection 2014.

Abstract

The generation of sensory neurons and hair cells of the inner ear is under tight control. Different members of the Hairy and Enhancer of Split genes (HES) are expressed in the inner ear, their full array of functions still not being disclosed. We have previously shown that zebrafish her9 acts as a patterning gene to restrict otic neurogenesis to an anterior domain. Here, we disclose the role of another her gene, her4, a zebrafish ortholog of Hes5 that is expressed in the neurogenic and sensory domains of the inner ear. The expression of her4 is highly dynamic and spatiotemporally regulated. We demonstrate by loss of function experiments that in the neurogenic domain her4 expression is under the regulation of neurogenin1 (neurog1) and the Notch pathway. Moreover, her4 participates in lateral inhibition during otic neurogenesis since her4 knockdown results in overproduction of the number of neurog1 and deltaB-positive otic neurons. In contrast, during sensorigenesis her4 is initially Notch-independent and induced by atoh1b in a broad prosensory domain. At later stages her4 expression becomes Notch-dependent in the future sensory domains but loss of her4 does not result in hair cell overproduction, suggesting that there other her genes can compensate its function.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / biosynthesis*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Ear, Inner / growth & development*
  • Ear, Inner / metabolism
  • Embryo, Nonmammalian
  • Embryonic Development*
  • Gene Expression Regulation, Developmental
  • Hair Cells, Auditory, Inner / metabolism
  • Nerve Tissue Proteins / biosynthesis
  • Nerve Tissue Proteins / genetics
  • Neurogenesis*
  • Receptors, Notch / biosynthesis
  • Receptors, Notch / genetics
  • Sensory Receptor Cells / metabolism
  • Signal Transduction / genetics
  • Zebrafish
  • Zebrafish Proteins / biosynthesis*
  • Zebrafish Proteins / genetics

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Nerve Tissue Proteins
  • Receptors, Notch
  • Zebrafish Proteins
  • her4.1 protein, zebrafish
  • neurog1 protein, zebrafish

Grants and funding

This work was supported by BFU2011-27006 from Ministerio de Ciencia e Innovacion (http://www.idi.mineco.gob.es/), MR was supported by FPI fellowship from Ministerio de Ciencia e Innovacion and LF was supported by FI from Agencia de gestio d'Ajuts Universitaris de Recerca(http://www10.gencat.cat/agaur_web/AppJava/catala/index.jsp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.