let-7 miRNAs inhibit CHD7 expression and control auditory-sensory progenitor cell behavior in the developing inner ear

Lale Evsen, Xiaojun Li, Shuran Zhang, Sharjil Razin, Angelika Doetzlhofer

Research output: Contribution to journalArticlepeer-review

Abstract

The evolutionarily conserved lethal-7 (let-7) microRNAs (miRNAs) are well-known activators of proliferative quiescence and terminal differentiation. However, in the murine auditory organ, let-7g overexpression delays the differentiation of mechano-sensory hair cells (HCs). To address whether the role of let-7 in auditory-sensory differentiation is conserved among vertebrates, we manipulated let-7 levels within the chicken auditory organ: the basilar papilla. Using a let-7 sponge construct to sequester let-7 miRNAs, we found that endogenous let-7 miRNAs are essential for limiting the self-renewal of HC progenitor cells. Furthermore, let-7b overexpression experiments revealed that, similar to mice, higher than normal let-7 levels slow/delay HC differentiation. Finally, we identify CHD7, a chromatin remodeler, as a candidate for mediating the repressive function of let-7 in HC differentiation and inner ear morphogenesis. Our analysis uncovered an evolutionarily conserved let-7-5p-binding site within the chicken Chd7 gene and its human and murine homologs, and we show that let-7g overexpression in mice limits CHD7 expression in the developing inner ear, retina and brain. Haploinsufficiency of CHD7 in humans causes CHARGE syndrome and attenuation of let-7 function may be an effective method for treating CHD7 deficiency.

Original languageEnglish (US)
JournalDevelopment (Cambridge, England)
Volume147
Issue number15
DOIs
StatePublished - Aug 14 2020

Keywords

  • Auditory
  • CHD7
  • Differentiation
  • Hair cell
  • Inner ear
  • let-7 miRNA

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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