INNER EAR DEVELOPMENT
Thomas Schimmang
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Neurotrophin signalling | FGF signalling | Gene profiling
The roles of neurotrophins and their receptors for innervation of the inner ear.Our studies have revealed which of the neurotrophins and their receptors, termed Trks are essential for the innervation of the inner ear in avians and mammals. Using viral gene transfer and the study of mouse mutants we could conclude that the neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) acting via their high-affinity receptors TrkB and TrkC control the survival and differentiation of auditory and vestibular sensory neurons. Recently, we have analysed the consequences of a lack of the TrkB receptor
and its ligand, the neurotrophin brain-derived neurotrophic factor (BDNF)
in the late postnatal or adult inner ear using mouse mutants. During early
postnatal development mutant animals show a lack of afferent innervation
on outer hair cells in the apical part of the cochlea, whereas nerve fibres
in the basal part are maintained. Strikingly, this phenotype is reversed
during subsequent maturation of the cochlea which results in a normal pattern
of outer hair cell innervation in the apex and loss of nerve fibres at
the base in adult mutants. Measurements of auditory brain stem responses
of these mice revealed a significant hearing loss. The observed innervation
patterns correlate with opposing gradients of BDNF and NT-3 expression
in cochlear neurons along the tonotopic axis.  The
reshaping of innervation thus may be controlled by autocrine signaling
between neurotrophins and their receptors in cochlear neurons. We
have now focussed on several animal models which mimic hearing impairment
which may occur during ageing in humans. A significant reduction of BDNF
transcripts in high-frequency processing cochlear neurons was observed
during aging, though this did not coincide with a major reduction of BDNF
protein. In contrast, BDNF protein in peripheral and central projections
was drastically reduced. Our results suggest that reduced BDNF protein
levels in auditory nerves over age may be a crucial factor in the altered
brainstem plasticity observed during presbycusis. Moreover, our results
indicate a substantial potential for reinnervation processes in the mature
cochlea
which may also be of relevance for treatment of hearing loss in humans.
The neurotrophins may be introduced via a viral system we have developed
which is based on Herpes simplex virus type I (HSV-1)-mediated gene. Due
to the neurotropism of HSV-1 this mode of transfer is especially suited
to express genes in the peripheral nervous system, including auditory sensory
neurons.
Recent publications:T. Schimmang, J. Tan, M. Müller, U. Zimmermann, K. Rohbock, I. Köpschall, A. Limberger, L. Minichiello and M. Knipper. (2003) Lack of BDNF and TrkB signaling leads to a spatial reinnervation reshaping of innervation and hearing loss. Development, 130, 4741-4750.*L. Rüttiger, *R. Panford-Walsh *T. Schimmang,
J. Tan, U. Zimmermann, K. Rohbock, I. Köpschall, A. Limberger, M.
Müller, J.–T. Fraenzer, J. Cimerman, and M. Knipper. (2007). BDNF
mRNA expression and protein localization are changed in age-related hearing
loss.
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