Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System

Sayyid, Zahra N.; Wang, Tian; Chen, Leon; Jones, Sherri M.; Cheng, Alan G.

doi:10.1016/j.celrep.2019.06.028

Cited by 60 publications

(87 citation statements)

References 59 publications

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“…Furthermore, it is required for generating the majority of glia in the antenna (Jhaveri et al 2000;Sen et al 2005). As the first known transcriptional factors expressed in inner ear hair cells, Atoh1 is required for fate determination of those cells, and misexpression of Atoh1 in other cells such as the glial-like support cells is sufficient to generate hair cells (Bermingham et al 1999;Ben-Arie et al 2000;Zheng and Gao 2000;Kawamoto et al 2003;Izumikawa et al 2005;Srivastava et al 2013;Sayyid et al 2019). In the cerebellum, Atoh1 is required for cerebellar granule neuron formation in addition to other neurons types in the parabrachial, lateral lemniscal, and deep cerebellar nuclei, while not found to be important for gliogenesis (Ben-Arie et al 1997;Wang et al 2005).…”

Section: Discussionmentioning

confidence: 99%

“…lin-32 was previously reported to regulate the neuronal fate specification of multiple cell lineages including neurons in the male tail (Portman and Emmons 2000;Zhao and Emmons 1995;Rojo Romanos et al 2017); CEPD, ADE and PDE dopaminergic neurons (Doitsidou et al 2008) and the URX oxygen-sensing neurons (Rojo Romanos et al 2017). Its mammalian homolog Atoh1 has also been implicated in the generation of inner ear hair cells (Bermingham et al 1999) and cerebellar granule neurons (Ben-Arie et al 1997), where overexpression can induce transdifferentiation of glial-like support cells into functioning hair cells in the cochlea and specify differentiation of mature cerebellar granule neurons at the expense of glial production in embryoid bodies (Izumikawa et al 2005;Srivastava et al 2013;Sayyid et al 2019). Furthermore, Atoh1 exhibits functional conservation with Drosophila atonal where it also promotes a neuronal fate (Ben-Arie et al 2000), while sensory precursors of the ato lineage generate the bulk of glia in the antenna (Jhaveri et al 2000;Sen et al 2005).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Gliogenesis bylin-32/Atoh1 inCaenorhabditis elegans

Zhang

Noma

Yan

2020

G3 Genes|Genomes|Genetics

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The regulation of gliogenesis is a fundamental process for nervous system development, as the appropriate glial number and identity is required for a functional nervous system. To investigate the molecular mechanisms involved in gliogenesis, we used C. elegans as a model and identified the function of the proneural gene lin-32/Atoh1 in gliogenesis. We found that lin-32 functions during embryonic development to negatively regulate the number of AMsh glia. The ectopic AMsh cells at least partially arise from cells originally fated to become CEPsh glia, suggesting that lin-32 is involved in the specification of specific glial subtypes. Moreover, we show that lin-32 acts in parallel with cnd-1/ NeuroD1 and ngn-1/ Neurog1 in negatively regulating an AMsh glia fate. Furthermore, expression of murine Atoh1 fully rescues lin-32 mutant phenotypes, suggesting lin-32/Atoh1 may have a conserved role in glial specification.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Regulation of Gliogenesis bylin-32/Atoh1 inCaenorhabditis elegans

Zhang

Noma

Yan

2020

G3 Genes|Genomes|Genetics

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“…Furthermore, it needs to be emphasized that our study was conducted in vitro and was limited to immature, early postnatal stages. While recent studies showed promise in regenerating vestibular hair cells in adult mice (9,82), the regeneration of cochlear hair cells in adult mice has proven thus far an impossible task (65) and reviewed in (83).…”

Section: Discussionmentioning

confidence: 99%

LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

Doetzlhofer

2020

Preprint

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Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells.However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mTOR activity. Employing murine cochlear organoid and explant cultures to model mitotic and non-mitotic mechanisms of hair cell generation, we show that loss of Lin28b function, due to its conditional deletion, or due to overexpression of the antagonistic miRNA let-7g, suppressed Akt-mTORC1 activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and non-mitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner. SIGNIFICANCE STATEMENTCochlear hair cell loss is a leading cause of deafness in humans and other mammals. In the immature cochlea lost hair cells are regenerated by neighboring glia-like supporting cells. However, for reasons unknown, such regenerative capacity is rapidly lost as supporting cells undergo maturation. Here we identify a direct link between LIN28B-mTOR activity and supporting cell plasticity. Mimicking later developmental stages, we found that loss of the RNA binding protein LIN28B attenuated mTOR signaling and rendered young, immature supporting cells incapable of producing hair cells. Conversely, we found Recent studies uncovered that as early as postnatal day 5/6 (P5/P6) murine cochlear supporting cells fail to regenerate hair cells in response to injury (14), inhibition of Notch signaling (26), or over-activation of Wnt/β-catenin signaling (27). What causes the rapid decline in supporting cell plasticity during the first postnatal week is currently unknown. We previously demonstrated that a regulatory circuit consisting of LIN28B and let-7 miRNAs modulates the production of new hair cells in stage P2 murine cochlear explants, with LIN28B promoting new hair cell production and let-7 miRNAs suppressing it (28). The closely related RNA binding proteins LIN28A and LIN28B (LIN28A/B) and members of the let-7 family of miRNAs belong to an evolutionary highly conserved network of genes, initially identified in C-elegans for their role in d...

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“…8; Sayyid et al, 2019, figure 2). The results of this study (Sayyid et al, 2019) show the importance of atoh1 gene expression in the hair cell regeneration response within the vestibular system.…”

Section: Future Directions For Applications Of Gene and Stem Cell Thementioning

confidence: 99%

Historical Aspects of Gene Therapy and Stem Cell Therapy in the Treatment of Hearing and Balance Disorder

Water

2020

The Anatomical Record

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This review presents many but not all the major historical events that have led to our current understanding of gene and stem cell therapies for the treatment of hearing and balance disorders in animal models of these disorders. In order to better understand the application of these emerging therapies to the treatment of inner ear disorders in a clinical setting, it has been necessary to provide some genetic and pathobiology backgrounds from both animal models and clinical disorders. The current focus and goal of gene and stem cell therapies are directed toward understanding the effective treatment of animal models that mimic human disorders of hearing and balance. This approach not only addresses the most effective ways to deliver the gene or stem cell therapies to affected inner ears, it also provides an assessment of the efficacy of the applied therapy(s) in achieving either partial or full restoration of either hearing and/or balance within the animal models receiving these therapeutic interventions. This review also attempts to present a realistic assessment of how close the research fields of gene and stem cell therapies are to application for the treatment of human disorders in a clinical setting. Progress made in developing these novel therapies toward clinical applications would not have been possible without the many pioneering studies and discoveries achieved by the investigators cited in this review. There were also many other excellent studies performed by gifted investigators that were not able to be included within this review. Anat Rec, 303:390–407, 2020. © 2019 American Association for Anatomy

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Atoh1 Directs Regeneration and Functional Recovery of the Mature Mouse Vestibular System

Cited by 60 publications

References 59 publications

Regulation of Gliogenesis bylin-32/Atoh1 inCaenorhabditis elegans

Regulation of Gliogenesis bylin-32/Atoh1 inCaenorhabditis elegans

LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

Historical Aspects of Gene Therapy and Stem Cell Therapy in the Treatment of Hearing and Balance Disorder

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