Biomedical subjects

Cyrille Sage

Publications and source records attributed to Cyrille Sage.

4 recordsLinked to original sources

PubMed2006

Essential role of retinoblastoma protein in mammalian hair cell development and hearing.

The retinoblastoma protein pRb is required for cell-cycle exit of embryonic mammalian hair cells but not for their early differentiation. However, its role in postnatal hair cells is unknown. To study the function of pRb in mature animals, we created a new conditional mouse model, with the Rb gene deleted primarily in the inner ear. Progeny survive up to 6 months. During early postnatal development, pRb(-/-) hair cells continue to divide and can transduce mechanical stimuli. However, adult pRb(-/-) mice exhibit profound hearing loss due to progressive degeneration of the organ of Corti. We show that pRb is required for the full maturation of cochlear outer hair cells, likely in a gene-specific manner, and is also essential for their survival. In addition, lack of pRb results in cell division in postnatal auditory supporting cells. In contrast, many pRb(-/-) vestibular hair cells survive and continue to divide in adult mice. Significantly, adult pRb(-/-) vestibular hair cells are functional, and pRb(-/-) mice maintain partial vestibular function. Therefore, the functional adult vestibular pRb(-/-) hair cells, derived from proliferation of postnatal hair cells, are largely integrated into vestibular pathways. This study reveals essential yet distinct roles of pRb in cochlear and vestibular hair cell maturation, function, and survival and suggests that transient block of pRb function in mature hair cells may lead to propagation of functional hair cells.

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PubMed2005

Proliferation of functional hair cells in vivo in the absence of the retinoblastoma protein.

In mammals, hair cell loss causes irreversible hearing and balance impairment because hair cells are terminally differentiated and do not regenerate spontaneously. By profiling gene expression in developing mouse vestibular organs, we identified the retinoblastoma protein (pRb) as a candidate regulator of cell cycle exit in hair cells. Differentiated and functional mouse hair cells with a targeted deletion of Rb1 undergo mitosis, divide, and cycle, yet continue to become highly differentiated and functional. Moreover, acute loss of Rb1 in postnatal hair cells caused cell cycle reentry. Manipulation of the pRb pathway may ultimately lead to mammalian hair cell regeneration.

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PubMed2004

Islet-1 expression in the developing chicken inner ear.

The cell types of the inner ear originate from the otic placode, a thickened layer of ectoderm adjacent to the developing hindbrain. The placode invaginates and forms the otic pit, which pinches off as a small vesicle called the otocyst. Presumptive cochleovestibular neurons delaminate from the anterior ventral part of the otocyst and form the cochleovestibular ganglion of the inner ear. Here we show that the LIM/homeodomain protein islet-1 is expressed in cells of the ventral part of the otic placode and that this ventral expression is maintained at the otic pit and the otocyst stages. Auditory and vestibular neurons originate from this islet-1-positive zone of the otocyst, and these neurons maintain islet-1 expression until adulthood. We also demonstrate that islet-1 becomes up-regulated in the presumptive sensory epithelia of the inner ear in regions that are defined by the expression domains of BMP4. The up-regulation of islet-1 in developing inner ear hair and supporting cells is accompanied by down-regulation of Pax-2 in these cell types. Islet-1 expression in hair and supporting cells persists until early postnatal stages, when the transcriptional regulator is down-regulated in hair cells. Our data is consistent with a role for islet-1 in differentiating inner ear neurons and sensory epithelia cells, perhaps in the specification of cellular subtypes in conjunction with other LIM/homeodomain proteins.

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PubMed2002

Distribution of alpha-amino-3-hydroxy-5-methyl-4 isoazolepropionic acid and N-methyl-D-aspartate receptor subunits in the vestibular and spiral ganglia of the mouse during early development.

We investigated the distribution of the glutamate receptor subunits, alpha-amino-3-hydroxy-5-methyl-4 isoazolepropionic acid (AMPA) GluR2 and GluR2/R3, and N-methyl-D-aspartate (NMDA) NR1, and the timing of their appearance during early development of the mouse vestibular and spiral ganglia. NMDA NR1 was the first to be expressed, in the statoacoustic ganglion neurons on E11. GluR2/R3 immunoreactivity was detected in these neurons on E12. This signal probably corresponded exclusively to GluR3, as no signal was obtained for GluR2 alone at this stage. The appearance of these proteins began much earlier than previously reported. GluR2 staining was observed later, on E14 in the vestibular neurons and on E17 in the spiral neurons. The sequence in which these three glutamate receptors appeared suggested possible differences in their roles in the establishment of neuronal circuitry in the inner ear sensory epithelia. The production of NR1 and GluR2/R3 began during the early period of neuron growth and fasciculation. GluR2 appeared later and its expression paralleled synaptogenesis in the vestibular sensory epithelia and in the organ of Corti.

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