Varitint-waddler (Va andVaA very common cause of deafness is the loss of hair cells, which degenerate because of environmental factors or genetic mutations. Varitint-waddler (Va) mice have a mutation that causes an alanine-to-proline substitution (A419P) in the fifth transmembrane domain of TRPML3, a presumed ion channel. A second allele, Va J , contains the A419P mutation in cis to an I362T mutation (1). The earliest sign of inner ear damage in Va mice is hair cell degeneration, which begins in embryogenesis as hair cells differentiate and continues postnatally. During degeneration, the hair cells bulge out of the apical side of the epithelium and become extruded. Eventually these mice also develop abnormalities in supporting cells, in the tectorial membrane, and in the stria vascularis and in the endocochlear potential that they help generate. The defects of Va J mice are similar although less severe, suggesting that the mutation I362T attenuates the effects of A419P (1-3). A comprehensive examination of TRPML3 expression in inner ear has not been published. Expression of TRPML3 protein in hair cells was suggested by immunocytochemical methods, although results for other inner ear cell types were not reported (1).Mutations in two other TRP channels, Drosophila TRP and human TRPML1 (mutations in which cause mucolipidosis type IV), are associated with degeneration of the retina. In both cases, the channels seem necessary for cellular viability, because recessive, loss-of-function mutations cause degeneration (4, 5).By contrast, the Va and Va J mutations in TRPML3 are semidominant, although it remains unclear whether this is due to gain-of-function, haploinsufficiency, or dominant-negative effects (1, 6). ResultsWe first established which cells expressed TRPML3 in the inner ear of wild-type mice. In situ hybridization on mouse inner ear using probes from two nonoverlapping regions of TRPML3 mRNA gave identical results [ Fig. 1 and supporting information (SI) Fig. 6]. TRPML3 mRNA was most abundant in the marginal cells of the cochlear stria vascularis and the dark cells of the vestibule (Fig. 1 i, l, and m and SI Fig. 6 i, l, and m). Both cell types are involved in producing the endolymph and therefore the endocochlear potential (7-9). This expression pattern is in keeping with the reduced stria vascularis and the rounding up and loss of the cytoplasmic processes of its marginal cells in Va/Va and Va/ϩ mice (2) and with the reduced endocochlear potentials of the Va J mutants (1, 3).In addition, other cells that line the cochlear scala media and the connected vestibular endolymphatic spaces expressed TRPML3 mRNA, including (i) supporting cells at the marginal part of the lesser epithelial ridge (Hensen and Claudius cells), which in Va and Va J mice (homozygotes and heterozygotes) appear undifferentiated or degenerate ( Fig. 1i and SI Fig. 6i); (ii) cells of the spiral limbus that produce the tectorial membrane, which in Va mice develops abnormally and fails to attach to the reticular lamina ( Fig. 1i and SI Fig. 6i...
Summary Intense noise damages the cochlear organ of Corti, particularly the outer hair cells (OHCs)[1], however this epithelium is not innervated by nociceptors of somatosensory ganglia, which detect damage elsewhere in the body. The only sensory neurons innervating the organ of Corti originate from the spiral ganglion, roughly 95% of which innervate exclusively inner hair cells (IHCs)[2-4]. Upon sound stimulation, IHCs release glutamate to activate AMPA-type receptors on these myelinated type-I neurons, which carry the neuronal signals to the cochlear nucleus. The remaining spiral ganglion cells (type-IIs) are unmyelinated and contact OHCs[2-4]. Their function is unknown. Using immunoreactivity to cFos, we documented neuronal activation in the brainstem of Vglut3−/− mice, in which the canonical auditory pathway (activation of type-I afferents by glutamate released from inner hair cells) is silenced[5, 6]. In these deaf mice, we found responses to noxious noise, that damages hair cells, but not to innocuous noise, in neurons of the cochlear nucleus, but not in the vestibular or trigeminal nuclei. This response originates in the cochlea and not in other areas also stimulated by intense noise (middle ear and vestibule) as it was absent in CD1 mice with selective cochlear degeneration but normal vestibular and somatosensory function. These data imply the existence of an alternative neuronal pathway from cochlea to brainstem that is activated by tissue-damaging noise and does not require glutamate release from IHCs. This detection of noise-induced tissue damage, possibly by type-II cochlear afferents, represents a novel form of sensation we term auditory nociception.
INSM1 is a zinc-finger protein expressed in the developing nervous system and pancreas as well as in medulloblastomas and neuroendocrine tumors. With in situ hybridization combined with immunohistochemistry, we detected INSM1 mRNA in all embryonic to adult neuroproliferative areas examined: embryonic neocortex, ganglionic eminence, midbrain, retina, hindbrain, and spinal cord; autonomic, dorsal root, trigeminal and spiral ganglia; olfactory and vomeronasal organ epithelia; postnatal cerebellum; and juvenile to adult subgranular zone of dentate gyrus, subventricular zone, and rostral migratory stream leading to olfactory bulb. In most of these neurogenic areas, subsets of neuronal progenitors and nascent, but not mature, neurons express INSM1. For example, in developing cerebellum, INSM1 is present in proliferating progenitors of the outer external granule layer (EGL) and in postmitotic cells of the inner EGL, but not in mature granule cell neurons. Also, lining the neural tube from spinal cord to neocortex in mouse as well as human embryos, cells undergoing mitosis apically do not express INSM1. By contrast, nonsurface progenitors located in the basal ventricular and/or subventricular zones express INSM1. Whereas apical progenitors are proliferative and generate one or two additional progenitors, basal progenitors are thought to divide terminally and symmetrically to produce two neurons. The nematode ortholog of INSM1, EGL-46, is expressed during terminal symmetric neurogenic divisions and regulates the termination of proliferation. We propose that, in mice and humans, INSM1 is likewise expressed transiently during terminal neurogenic divisions, from late progenitors to nascent neurons, and particularly during symmetric neuronogenic divisions.
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