Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear

Bok, Jinwoong; Dolson, Diane K.; Hill, Patrick; Rüther, Ulrich; Epstein, Douglas J.; Wu, Doris K.

doi:10.1242/dev.000760

Cited by 105 publications

(155 citation statements)

References 49 publications

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“…We investigated this possibility by analyzing the Foxg1 Cre ; Shh lox/− inner ears for expression of Msx1, a marker for the apical region of the cochlear duct (11). Our results show that Msx1 expression in Foxg1 Cre ; Shh lox/− mutants is comparable to that in controls at both E11.5 and E15.5 (Fig.…”

Section: Moderate Premature Cell Cycle Exit Of Hair Cell Precursors Imentioning

confidence: 82%

“…Foxg1 is expressed in the otocyst and CVG (16). Based on published cre reporter activities, all three cre strains should ablate Shh expression in the CVG (16)(17)(18) while sparing its expression in the notochord and floor plate, two sources of Shh thought to be required for specification of cochlear identity (10,11).…”

Section: Resultsmentioning

confidence: 99%

“…It has been shown that cochlear duct patterning requires a gradient of Shh signaling that is highest at the apex and lowest at the base (11). This graded Shh signal has been attributed to the otocyst's proximity to the notochord and floor plate.…”

Section: Moderate Premature Cell Cycle Exit Of Hair Cell Precursors Imentioning

confidence: 99%

“…Shh secreted from the notochord and floor plate are required for patterning in the cochlea (10)(11)(12). Additionally, Shh is expressed in the spiral ganglion that innervates cochlear HCs, and studies conducted using a Shh-cre-Gfp reporter strain indicate that Shh expression in the developing spiral ganglion becomes concentrated near the apex of the growing cochlear duct over time (13).…”

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confidence: 99%

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Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells

Bok

Zenczak

Hwang

et al. 2013

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

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111

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Neural precursor cells of the central nervous system undergo successive temporal waves of terminal division, each of which is soon followed by the onset of cell differentiation. The organ of Corti in the mammalian cochlea develops differently, such that precursors at the apex are the first to exit from the cell cycle but the last to begin differentiating as mechanosensory hair cells. Using a tissuespecific knockout approach in mice, we show that this unique temporal pattern of sensory cell development requires that the adjacent auditory (spiral) ganglion serve as a source of the signaling molecule Sonic hedgehog (Shh). In the absence of this signaling, the cochlear duct is shortened, sensory hair cell precursors exit from the cell cycle prematurely, and hair cell differentiation closely follows cell cycle exit in a similar apical-to-basal direction. The dynamic relationship between the restriction of Shh expression in the developing spiral ganglion and its proximity to regions of the growing cochlear duct dictates the timing of terminal mitosis of hair cell precursors and their subsequent differentiation.morphogenesis | Atoh1 | tonotopy T he mammalian cochlea, a coiled sensory end organ of hearing, contains a specialized mechanosensory epithelium (organ of Corti) consisting of hair cells (HCs) and nonsensory supporting cells. Sound frequency discrimination in mammals begins in the cochlea with a frequency-place code, such that specific frequencies elicit maximal responses of the organ of Corti at different points along its longitudinal (basal-apical) axis, a phenomenon known as tonotopy. Many structural and molecular features of the mature organ of Corti that vary along the longitudinal (tonotopic) axis, including stiffness of the basilar membrane and size and shape of the sensory HCs and their associated stereocilia (1, 2), have been implicated as contributing factors in frequency discrimination. The developmental bases of tonotopy remain obscure, however (3).A possible developmental influence on tonotopy is the wellcharacterized dynamic of apical (low-frequency sensing) precursors exiting early from the cell cycle, evident at embryonic day (E) 12.5 in mice, followed by a wave-like spread of terminal mitosis toward the base (high-frequency sensing), with cells completing cell cycle exit (CCE) by E14.5 (Fig. 1A) (4, 5). In contrast, early markers of HC differentiation, such as atonal homolog 1 (Atoh1), first appear at the midbase at E13.5 and spread bidirectionally along the developing organ of Corti (Fig. 1A) (6). Consequently, apically located HC precursors remain in a postmitotic, undifferentiated state for a longer period than their more basal counterparts. This unusual pattern of cellular regulation is in stark contrast to the neural precursors in the cortex and retina, in which each neuronal subtype has a specific timing of terminal mitosis, followed closely by its differentiation (7,8).Gradients of secreted molecules are important for patterning and cell fate specification during embryogenesis. Although t...

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Section: Moderate Premature Cell Cycle Exit Of Hair Cell Precursors Imentioning

confidence: 82%

Section: Resultsmentioning

confidence: 99%

Section: Moderate Premature Cell Cycle Exit Of Hair Cell Precursors Imentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells

Bok

Zenczak

Hwang

et al. 2013

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

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111

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“…Whereas the GLI3 repressor is known to exert a broad and essential function in development by antagonizing SHH activity, emerging studies have also established important developmental roles for a GLI3 activator function in proper patterning of the ventral spinal cord, brain, limb digits, inner ear, and sclerotome (18,(20)(21)(22)(23). Nonetheless, relatively few studies have focused on the mechanism by which GLI3 stimulates target gene transcription in the nucleus.…”

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confidence: 99%

MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

Zhou

Spaeth

Kim

et al. 2012

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

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Recurrent missense mutations in the RNA polymerase II Mediator subunit MED12 are associated with X-linked intellectual disability (XLID) and multiple congenital anomalies, including craniofacial, musculoskeletal, and behavioral defects in humans with FG (or Opitz-Kaveggia) and Lujan syndromes. However, the molecular mechanism(s) underlying these phenotypes is poorly understood. Here we report that MED12 mutations R961W and N1007S causing FG and Lujan syndromes, respectively, disrupt a Mediator-imposed constraint on GLI3-dependent Sonic Hedgehog (SHH) signaling. We show that the FG/R961W and Lujan/N1007S mutations disrupt the gene-specific association of MED12 with a second Mediator subunit, CDK8, identified herein to be a suppressor of GLI3 transactivation activity. In FG/R961W and Lujan/N1007S patient-derived cells, we document enhanced SHH pathway activation and GLI3-target gene induction coincident with impaired recruitment of CDK8 onto promoters of GLI3-target genes, but not non-GLI3-target genes. Together, these findings suggest that dysregulated GLI3-dependent SHH signaling contributes to phenotypes of individuals with FG and Lujan syndromes and further reveal a basis for the gene-specific manifestation of pathogenic mutations in a global transcriptional coregulator.

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Specification of cell fate in the mammalian cochlea

Driver

Kelley

2009

Birth Defects Research Pt C

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Mammalian auditory sensation is mediated by the organ of Corti, a specialized sensory epithelium found in the cochlea of the inner ear. Proper auditory function requires that the many different cell types found in the sensory epithelium be precisely ordered within an exquisitely patterned cellular mosaic. The development of this mosaic depends on a series of cell fate decisions that transform the initially nearly uniform cochlear epithelium into the complex structure of the mature organ of Corti. The prosensory domain, which contains the progenitors of both the mechanosensory hair cells and their associated supporting cells, first becomes distinct from both the neural and the nonsensory domains. Further cell fate decisions subdivide prosensory cells into populations of inner and outer hair cells, and several different types of supporting cells. A number of different signaling pathways and transcription factors are known to be necessary for these developmental processes; in this review we will summarize these results with an emphasis on recent findings.

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Opposing gradients of Gli repressor and activators mediate Shh signaling along the dorsoventral axis of the inner ear

Cited by 105 publications

References 49 publications

Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells

Auditory ganglion source of Sonic hedgehog regulates timing of cell cycle exit and differentiation of mammalian cochlear hair cells

MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

Specification of cell fate in the mammalian cochlea

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