Dataset Information

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

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. TGF?/SMAD is the best-known pathway linked to the induction of developmentally programmed cell senescence. Here, we studied if TGF?2 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 TGF?2 and a selective TGF-? receptor type-I inhibitor, we show that TGF?2 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 TGF?2 reduces proliferation, and induces differentiation and neuritogenesis of neuroblasts, without altering cell death. Our studies highlight the roles of TGF?2 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.

SUBMITTER: Magarinos M

PROVIDER: S-EPMC7461926 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

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

Frontiers in cellular neuroscience 20200817

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 b ...[more]

PMID: 32973450

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Project description:Using immunostaining and confocal microscopy, we here provide the first detailed description of otic neurogenesis in Xenopus laevis. We show that the otic vesicle comprises a pseudostratified epithelium with apicobasal polarity (apical enrichment of Par3, aPKC, phosphorylated Myosin light chain, N-cadherin) and interkinetic nuclear migration (apical localization of mitotic, pH3-positive cells). A Sox3-immunopositive neurosensory area in the ventromedial otic vesicle gives rise to neuroblasts, which delaminate through breaches in the basal lamina between stages 26/27 and 39. Delaminated cells congregate to form the vestibulocochlear ganglion, whose peripheral cells continue to proliferate (as judged by EdU incorporation), while central cells differentiate into Islet1/2-immunopositive neurons from stage 29 on and send out neurites at stage 31. The central part of the neurosensory area retains Sox3 but stops proliferating from stage 33, forming the first sensory areas (utricular/saccular maculae). The phosphatase and transcriptional coactivator Eya1 has previously been shown to play a central role for otic neurogenesis but the underlying mechanism is poorly understood. Using an antibody specifically raised against Xenopus Eya1, we characterize the subcellular localization of Eya1 proteins, their levels of expression as well as their distribution in relation to progenitor and neuronal differentiation markers during otic neurogenesis. We show that Eya1 protein localizes to both nuclei and cytoplasm in the otic epithelium, with levels of nuclear Eya1 declining in differentiating (Islet1/2+) vestibulocochlear ganglion neurons and in the developing sensory areas. Morpholino-based knockdown of Eya1 leads to reduction of proliferating, Sox3- and Islet1/2-immunopositive cells, redistribution of cell polarity proteins and loss of N-cadherin suggesting that Eya1 is required for maintenance of epithelial cells with apicobasal polarity, progenitor proliferation and neuronal differentiation during otic neurogenesis.

Dataset Information

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

Publications

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

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