Genetic dissection of Hoxb1 function in the developing mouse auditory system

The central auditory pathway consists of sensory nuclei that transmit the ascending acoustic information and efferent motoneurons that modulate primary afferent responses. It is known that rhombomere 4 (r4) and Hoxb1are involved in the development of the central circuit that allows the perception and amplification of sound. Moreover, patients with mutations in the HOXB1 locus do suffer of auditory deficiencies1. The sensory area of the Corti organ consists of two cell types: the inner hair cells (IHC) and the outer hair cells (OHC). IHCs are the major detectors of auditory stimuli and are innervated by lateral olivocochlear motoneurons (LOC), whereas the medial olivocochlear motoneurones (MOCs) synapse with OHCs involved in the cochlear amplification process. Both LOC and MOC are under the control of Hoxb1 to develop. We previously showed that MOC and LOC are absent in Hoxb1null mutants; mice have hearing impairments and a degeneration of OHCs. Scansion electron microscopy (SEM) investigations show a considerable disorganization of OHC stereocilia and cell loss at the apical level where low frequency sounds are normally perceived2. Degeneration of OHCs may be caused by the absence of synaptic/trophic stimulation of OHCs from the MOCs during a postnatal critical period3. To test this hypothesis and exclude a possible contribution of central auditory nuclei in this phenotype, we analyzed by SEM conditional Hoxb1 mutants (Ptf1acre Hoxb1 Flox/Flox; Atoh1cre Hoxb1 Flox/Flox) in which Hoxb1 is eliminated in dorsal/ sensory structures involved in the acoustic pathway. Our preliminary data show that in the presence of Hoxb1 in the ventral/ motor domain, where MOC and LOC motoneurons develop, but in the absence of Hoxb1 in sensory central nuclei, OHCs show a regular morphology and fail to reproduce the severe phenotype observed in Hoxb1null mutants. To ultimately confirm a role of MOCs as major effectors, Hoxb1 function will be abolished in theventral domain of r4 using a motorneuron-specifc Cre-recombinase line.