Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development

Tateya, Tomoko; Imayoshi, Itaru; Tateya, Ichiro; Ito, Juichi; Kageyama, Ryoichiro

doi:10.1016/j.ydbio.2011.01.038

Cited by 88 publications

(94 citation statements)

References 33 publications

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“…Notch signaling, however, does not seem to be required for proliferation. Conditional deletion of Rbpj, a crucial transcription factor required for Notch signaling, as well as triple knockdowns of Hes1, Hes5 and Hey1, had no effect on prosensory proliferation or the number of prosensory cells that formed (Tateya et al, 2011;Yamamoto et al, 2011), suggesting that the proliferative effect of Wnt/-catenin might be independent of Notch signaling.…”

Section: Research Articlementioning

confidence: 99%

“…In addition to Sox2, Notch signaling is also known to function in OC development (Brooker et al, 2006;Hayashi et al, 2008;Kiernan et al, 2006;Pan et al, 2010;Tateya et al, 2011). The Notch ligand Jag1 has been shown to be required for cochlear prosensory formation (Pan et al, 2010), and, in other systems, Wnt/-catenin signaling regulates the expression of Jag1 Rodilla et al, 2009).…”

Section: Research Articlementioning

confidence: 99%

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A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

et al. 2012

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The canonical Wnt/β-catenin signaling pathway is known to play crucial roles in organogenesis by regulating both proliferation and differentiation. In the inner ear, this pathway has been shown to regulate the size of the otic placode from which the cochlea will arise; however, direct activity of canonical Wnt signaling as well as its function during cochlear mechanosensory hair cell development had yet to be identified. Using TCF/Lef:H2B-GFP reporter mice and transfection of an independent TCF/Lef reporter construct, we describe the pattern of canonical Wnt activity in the developing mouse cochlea. We show that prior to terminal mitosis, canonical Wnt activity is high in early prosensory cells from which hair cells and support cells will differentiate, and activity becomes reduced as development progresses. Using an in vitro model we demonstrate that Wnt/β-catenin signaling regulates both proliferation and hair cell differentiation within the developing cochlear duct. Inhibition of Wnt/β-catenin signaling blocks proliferation during early mitotic phases of development and inhibits hair cell formation in the differentiating organ of Corti. Conversely, activation increases the number of hair cells that differentiate and induces proliferation in prosensory cells, causing an expansion of the Sox2-positive prosensory domain. We further demonstrate that the induced proliferation of Sox2-positive cells may be mediated by the cell cycle regulator cyclin D1. Lastly, we provide evidence that the mitotic Sox2-positive cells are competent to differentiate into hair cells. Combined, our data suggest that Wnt/β-catenin signaling has a dual function in cochlear development, regulating both proliferation and hair cell differentiation.

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Section: Research Articlementioning

confidence: 99%

Section: Research Articlementioning

confidence: 99%

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

et al. 2012

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“…Hes1, Hes5, and Hey1 are expressed in the developing cochlea of the inner ear, and they cooperatively inhibit the formation of hair cells, which are sensory neurons. Inactivation of these genes leads to disorganized cell alignment and polarity and to hearing loss due to hair cell overproduction (Tateya, et al, 2011). In the developing retina, Hes1 and Hes5 function downstream of both Shh and Notch signaling, inhibit the activity of proneural bHLH genes such as Mash1 and Math3, and maintain progenitor cell populations (Wall, et al, 2009;Ohtsuka, et al, 2001).…”

Section: Roles Of Hes Factors In Various Tissuesmentioning

confidence: 99%

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Kobayashi

Kageyama

2014

Current Topics in Developmental Biology

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Hes genes, encoding basic helix-loop-helix (HLH) transcriptional repressors, are mammalian homologues of Drosophila hairy and Enhancer of split genes, both of which are required for normal neurogenesis in Drosophila. There are seven members in the human Hes family, Hes1 to Hes7, which are expressed in many tissues and play various roles mainly in development. All Hes proteins have three conserved domains: basic HLH (bHLH), Orange, and WRPW domains. The basic region binds to target DNA sequences while the HLH region forms homo-and hetero-dimers with other bHLH proteins, the Orange domain is responsible for the selection of partners during heterodimer formation, and the WRPW domain recruits co-repressors. Hes1, Hes5, and Hes7 are known as downstream effectors of canonical Notch signaling, which regulates cell differentiation via cell-cell interaction. Hes factors regulate many events in development by repressing the expression of target genes, many of which encode transcriptional activators that promote cell differentiation. For example, Hes1, Hes3, and Hes5 are highly expressed by neural stem cells, and inactivation of these genes results in insufficient maintenance of stem cell proliferation and prematurely promotes neuronal differentiation. Recently, it was shown that the expression dynamics of Hes1 plays crucial roles in proper developmental timings and fate determination steps of embryonic stem cells and neural progenitor cells. Here we discuss some key features of Hes factors in development and diseases.

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“…Kip1 (Cdkn1b -Mouse Genome Informatics) and Prox1 staining, samples were heated in 10 mM sodium citrate at 90°C for 10 minutes prior to the staining procedure (Tateya et al, 2011). For staining of whole-mount preparations of the cochleae, cochlear ducts were opened to expose the developing sensory epithelia prior to the staining procedure (Yamamoto et al, 2009).…”

Section: Histochemistry and In Situ Hybridizationmentioning

confidence: 99%

Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea

et al. 2013

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SUMMARYMechanosensory hair cells and supporting cells develop from common precursors located in the prosensory domain of the developing cochlear epithelium. Prosensory cell differentiation into hair cells or supporting cells proceeds from the basal to the apical region of the cochleae, but the mechanism and significance of this basal-to-apical wave of differentiation remain to be elucidated. Here, we investigated the role of Hedgehog (Hh) signaling in cochlear development by examining the effects of up-and downregulation of Hh signaling in vivo. The Hh effector smoothened (Smo) was genetically activated or inactivated specifically in the developing cochlear epithelium after prosensory domain formation. Cochleae expressing a constitutively active allele of Smo showed only one row of inner hair cells with no outer hair cells (OHCs); abnormal undifferentiated prosensory-like cells were present in the lateral compartment instead of OHCs and their adjacent supporting cells. This suggests that Hh signaling inhibits prosensory cell differentiation into hair cells or supporting cells and maintains their properties as prosensory cells. Conversely, in cochlea with the Smo conditional knockout (Smo CKO), hair cell differentiation was preferentially accelerated in the apical region. Smo CKO mice survived after birth, and exhibited hair cell disarrangement in the apical region, a decrease in hair cell number, and hearing impairment. These results indicate that Hh signaling delays hair cell and supporting cell differentiation in the apical region, which forms the basal-to-apical wave of development, and is required for the proper differentiation, arrangement and survival of hair cells and for hearing ability.

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Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development

Cited by 88 publications

References 33 publications

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

A dual function for canonical Wnt/β-catenin signaling in the developing mammalian cochlea

Expression Dynamics and Functions of Hes Factors in Development and Diseases

Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea

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