Otic Neurogenesis Is Regulated by TGFβ in a Senescence-Independent Manner.

Marta Magariños,Maria R Aburto,Raquel Barajas-Azpeleta,Isabel Varela-Nieto

doi:10.3389/fncel.2020.00217

Abstract

Cellular senescence has classically been associated with aging. Intriguingly, recent studies have also unraveled key roles for senescence in embryonic development, regeneration, and reprogramming. Developmental senescence has been reported during embryonic development in different organisms and structures, such as the endolymphatic duct during inner ear development of mammals and birds. However, there is no study addressing the possible role of senescence on otic neurogenesis. TGFβ/SMAD is the best-known pathway linked to the induction of developmentally programmed cell senescence. Here, we studied if TGFβ2 induces cellular senescence during acoustic-vestibular-ganglion (AVG) formation. Using organotypic cultures of AVG, and characterizing different stages of otic neurogenesis in the presence of TGFβ2 and a selective TGF-β receptor type-I inhibitor, we show that TGFβ2 exerts a powerful action in inner ear neurogenesis but, contrary to what we recently observed during endolymphatic duct development, these actions are independent of cellular senescence. We show that TGFβ2 reduces proliferation, and induces differentiation and neuritogenesis of neuroblasts, without altering cell death. Our studies highlight the roles of TGFβ2 and cellular senescence in the precise regulation of cell fate within the developing inner ear and its different cell types, being their mechanisms of action highly cell-type dependent.

Highlights

The vertebrate inner ear is a complex sensory organ responsible for the perceptions of sound and balance
Our results show that TGFβ2 exerts a powerful action in the inner ear neurogenesis, but these actions are independent of cellular senescence, contrary to what we recently observed during endolymphatic duct development
TGFβ2 is a potent regulator of cellular senescence during inner ear development, which has been proven to be an essential process for proper morphogenesis of the endolymphatic duct (Gibaja et al, 2019)

Summary

Introduction

The vertebrate inner ear is a complex sensory organ responsible for the perceptions of sound and balance. Programmed senescence acts together with apoptosis in the elimination of unwanted cells as well as in patterning and morphogenesis (Lorda-Diez et al, 2015) It shares most of the cellular characteristics of replicative and oncogeneinduced senescence, such as arrested proliferation, increased SAβG staining, and a secretory phenotype. Current data suggest that senescent cells may have multiple functions in the embryo (Da Silva-Álvarez et al, 2019; Rhinn et al, 2019) These development-associated senescent cells arise in very precise patterns in time and space, before subsequently disappearing, pointing to a tightly regulated appearance and removal of these cells (Muñoz-Espín et al, 2013; Storer et al, 2013; Davaapil et al, 2017). Some of the structures that have been associated with programmed cellular senescence are the endolymphatic sac, the mesonephros, the neural tube, the apical ectodermal ridge, the interdigital tissue and the endolymphatic duct (Muñoz-Espín et al, 2013; Storer et al, 2013; Lorda-Diez et al, 2015; Gibaja et al, 2019; Rhinn et al, 2019)

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