BMP Signaling Is Necessary for Patterning the Sensory and Nonsensory Regions of the Developing Mammalian Cochlea

Ohyama, Takahiro; Basch, Martín L.; Mishina, Yuji; Lyons, Karen M.; Segil, Neil; Groves, Andrew K.

doi:10.1523/jneurosci.3547-10.2010

Cited by 151 publications

(231 citation statements)

References 61 publications

(85 reference statements)

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“…Bmp signaling influences hair cell differentiation during chicken and mouse inner ear development (70)(71)(72)(73). During zebrafish hair cell regeneration, bmp5 is up-regulated between 1 and 5 h after hair cell death ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

152

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Deafness caused by the terminal loss of inner ear hair cells is one of the most common sensory diseases. However, nonmammalian animals (e.g., birds, amphibians, and fish) regenerate damaged hair cells. To understand better the reasons underpinning such disparities in regeneration among vertebrates, we set out to define at high resolution the changes in gene expression associated with the regeneration of hair cells in the zebrafish lateral line. We performed RNA-Seq analyses on regenerating support cells purified by FACS. The resulting expression data were subjected to pathway enrichment analyses, and the differentially expressed genes were validated in vivo via whole-mount in situ hybridizations. We discovered that cell cycle regulators are expressed hours before the activation of Wnt/β-catenin signaling following hair cell death. We propose that Wnt/β-catenin signaling is not involved in regulating the onset of proliferation but governs proliferation at later stages of regeneration. In addition, and in marked contrast to mammals, our data clearly indicate that the Notch pathway is significantly down-regulated shortly after injury, thus uncovering a key difference between the zebrafish and mammalian responses to hair cell injury. Taken together, our findings lay the foundation for identifying differences in signaling pathway regulation that could be exploited as potential therapeutic targets to promote either sensory epithelium or hair cell regeneration in mammals.signaling pathway analysis | RNA sequencing | neuromast | Jak/Stat3 | cdkn1b

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Section: Resultsmentioning

confidence: 99%

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Jiang

Romero‐Carvajal

Haug

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

137

152

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“…Cells in the lateral compartment of R26-SmoM2 cochlear epithelium expressed p27 Kip1 , and the nuclei of p27 Kip1 -positive cells remained stratified, similar to wildtype E13.5-E14.5 prosensory epithelium (Fig. 4R) (Hayashi et al, 2008a;Ohyama et al, 2010). These results suggest that prosensory cell-like cells are maintained in the lateral compartment by excessive Hh signaling in R26-SmoM2 cochlear epithelium.…”

Section: Research Article Development 140 (18) P27mentioning

confidence: 52%

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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“…Sox2 marks a sensory-competent region (Kiernan et al, 2005) and we can borrow nomenclature used in the chicken to orient its radial dimension: the anterior edge is close to the forming cochleovestibular ganglion and is defined as the neural side, whereas the opposite, posterior edge, is defined as the abneural side. Already, asymmetric gene expression is observed, with a narrow strip of Bmp4 abneurally and a gradient of Fgf10 that peaks at the neural edge (Ohyama et al, 2010). Over the next few days, the Bmp4 domain expands and will become the outer sulcus (see Glossary, Box 1) (Morsli et al, 1998), while the Fgf10 domain sharpens, is confined to Kölliker's organ (see Glossary, Box 1), and will subsequently become the greater epithelial ridge.…”

Section: Establishing Gradients and Boundaries In The Developing Cochleamentioning

confidence: 99%

“…Genetic reduction of the copy number of two BMP receptors, or treatment of organ cultures with BMP activators or inhibitors, offers insight into the responsiveness of cochlear progenitors to variations in BMP signaling (Ohyama et al, 2010). Culturing E11.5 mouse cochlear explants in high concentrations of BMP4 (50 ng/ml) induces genes that mark outer sulcus fate, whereas low or no BMP signaling induces markers of Kölliker's organ.…”

Section: Bmp4 and Subdivision Boundariesmentioning

confidence: 99%

“…Complicating the interpretation is the appearance of Nog transcripts in the outer sulcus domain by E15.5 (Bok et al, 2007a;Hwang et al, 2010), together with crossveinless 2 (or BMP-binding endothelial regulator, Bmper), which can either enhance or attenuate BMP signaling (Ambrosio et al, 2008;Serpe et al, 2008;Zhang et al, 2008). BMP4 also positively regulates its own transcription in the cochlea (Ohyama et al, 2010). Because Nog should repress BMP4 efficacy or its realm of activity, Nog removal offers an alternative approach to examine BMP gain-of-function effects.…”

Section: Review Development 139 (2) Review Development 139 (2)mentioning

confidence: 99%

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Shaping sound in space: the regulation of inner ear patterning

2012

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There was an error in Development 139, 245-257.On p. 252, in the second paragraph of the section 'Establishing gradients and boundaries in the developing cochlea', it should read 'In adults…from high (basal) to low (apical).'The authors apologise to readers for this mistake. Development 139, 826 (2012) so is not yet available in most cases. This review will summarize recent findings on the identity of these signaling and morphogen molecules and how they are coordinated in space and time to generate the tissue and cellular architecture of the ear. From placode to ear -how graded signals turn ectoderm into the inner earThe entire inner ear and its associated sensory ganglia derive from the otic placode (see Glossary, Box 1). It is one of a series of cranial placodes that collectively give rise to all craniofacial sensory organs, the lens and a subset of cranial ganglia (Baker and Bronner-Fraser, 2001;Schlosser, 2010). The precursors of different placodes are distributed in an anterior-posterior (AP) sequence around the rostral neural plate (see Glossary, Box 1) termed the pre-placodal domain (PPD) (Schlosser, 2006;Streit, 2007). The PPD is induced by signals, such as FGFs, from both the neural plate and the underlying cranial mesoderm, and inhibition of both Wnt and BMP signaling is required to correctly position the PPD at the neural plate border and to prevent it from extending into the embryonic trunk (Kwon et al., 2010;Litsiou et al., 2005).It is now well established that FGF signals are both necessary and sufficient to induce early otic placode markers from competent pre-placodal ectoderm (Fig. 2) (Ohyama et al., 2007;Schimmang, 2007), although both the location of the FGF signals and the specific FGFs responsible for otic induction vary from species to species. The earliest markers of the future inner ear that are induced in response to FGF signaling are members of the paired homeoboxcontaining Pax2/5/8 transcription factor family -Pax8 in anamniotes and Pax2 in amniotes (Groves and Bronner-Fraser, 2000;Heller and Brandli, 1999;Ohyama and Groves, 2004;Pfeffer et al., 1998). Fate-mapping studies in mice and chick have suggested that although the Pax2-expressing domain is likely to contain all the progenitors of the inner ear, it also harbors cells that will give rise to the epibranchial placodes (see Glossary, Box 1) and epidermis (Ohyama and Groves, 2004;Ohyama et al., 2007;Streit, 2001). This Pax2-expressing progenitor domain has been termed the pre-otic field or the otic-epibranchial progenitor domain (OEPD) (Ladher et al., 2000;Freter et al., 2008).The refinement of the OEPD into distinct otic, epibranchial and epidermal territories is regulated by graded Wnt signals emanating from the midline (Fig. 2) (Ohyama et al., 2006). Examination of the cranial region of Wnt reporter mice revealed that OEPD cells closest to the neural plate, which are fated to form the otic placode, receive high levels of Wnt signaling, whereas more lateral OEPD cells, fated to form epidermis and the epibranchial placodes, receiv...

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BMP Signaling Is Necessary for Patterning the Sensory and Nonsensory Regions of the Developing Mammalian Cochlea

Cited by 151 publications

References 61 publications

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

Gene-expression analysis of hair cell regeneration in the zebrafish lateral line

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

Shaping sound in space: the regulation of inner ear patterning

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