A significantly increased risk for dominant sensorineural deafness in patients who have Hirschsprung disease (HSCR) caused by endothelin receptor type B and SOX10 has been reported. Despite the fact that c-RET is the most frequent causal gene of HSCR, it has not been determined whether impairments of c-Ret and c-RET cause congenital deafness in mice and humans. Here, we show that impaired phosphorylation of c-Ret at tyrosine 1062 causes HSCR-linked syndromic congenital deafness in c-Ret knockin (KI) mice. The deafness involves neurodegeneration of spiral ganglion neurons (SGNs) with not only impaired phosphorylation of Akt and NF-κB but decreased expression of calbindin D28k in inner ears. The congenital deafness involving neurodegeneration of SGNs in c-Ret KI mice was rescued by introducing constitutively activated RET. Taken together with our results for three patients with congenital deafness with c-RET-mediated severe HSCR, our results indicate that c-Ret and c-RET are a deafness-related molecule in mice and humans. spiral ganglion neuron | syndromic congenital deafness | tyrosine kinase A bout 30% of the 120 million people worldwide who suffer from congenital (early-onset) hearing loss are syndromic, and the remaining 70% are nonsyndromic (1-3). To elucidate the etiologies for the hearing losses, inner ears have been morphologically investigated as one of the target tissues. The inner ears contain the organ of Corti and the stria vascularis. The stria vascularis serves to maintain the endolymph potential. The organ of Corti, which consists of two kinds of sensory cells (inner hair cells and outer hair cells) is responsible for mechanotransduction, by which sound impulses are converted into neural impulses. Auditory information from the sensory cells is transmitted to spiral ganglion neurons (SGNs) as the primary carrier, followed by eventual transmission to the auditory cortex (1, 2

Impairments of endothelin receptor B (Ednrb

No abstract

No abstract

Auditory hypersensitivity may be, in part, due to impairment of inhibitory processing by the auditory brain center.

The development of facial nuclei in animal models of disease is poorly understood, but autism is sometimes associated with facial palsy. In the present study, to investigate migration of facial neurons and initial facial nucleus formation in an animal model of autism, rat embryos were treated with valproic acid (VPA) in utero at embryonic day (E) 9.5 and their facial nuclei were analyzed by in situ hybridization at E13.5, E14.5 and E15.5. Signals for Tbx20, which is expressed in early motor neurons, appeared near the floor plate at the level of the vestibular ganglion and extended caudolaterally, where they became ovoid in shape. This pattern of development was similar between control and VPA-exposed embryos. However, measurements of the migratory pathway and the size of the facial nuclei revealed that exposure to VPA hindered the caudal migration of neurons to the facial nuclei. Signals for cadherin 8, which is expressed in mature facial nuclei, revealed that exposure to VPA caused a significant reduction in the size of the facial nuclei. Our findings provide the first quantitative description of tangential migration and nucleus formation in the developing hindbrain in a rat model of autism.

Auditory hypersensitivity in autism is frequently observed in clinics. Dysfunction in the auditory brainstem has been suspected. We have established autism model rats using prenatal thalidomide exposure. Here we investigated whether abnormal response occurs in the brainstem following sound stimulus in autism model rats. Autism model rats were prepared by prenatal exposure to thalidomide on embryonic days 9 and 10 in pregnant rats. Then, the animals were exposed to 16‐kHz pure tone auditory stimulus and c‐Fos immunostaining was performed to examine the neuronal activity on postnatal day 49 to 51. Following sound stimulus, increased number of c‐Fos‐positive neurons was observed in the medial nucleus of the trapezoid body of autism model rats compared with the control rats. These results suggest that prenatal thalidomide might cause altered processing of auditory stimulus, leading to the characteristics of auditory hypersensitivity in autism.

No abstract