Hoxb1 FUNCTION IN THE DEVELOPING MOUSE AUDITORY SYSTEM RHOMBOMERE 4-DERIVED

Hoxb1 gene is essential for the specification of rhombomere 4 (r4)-derived auditory sensory and motor neurons contributing to the formation of specific auditory subcircuits. As we previouslyshowed, R4 largely contributes to the motor cochlear efferentneurons and Hoxb1 loss strongly prevents the proper development of the auditory system. As a matter of fact, Hoxb1 mutants display an increased auditory threshold that leads to severe hearing impairments. It is known that medial olivo-cochlear motoneurons (MOCs) which synapse with outer hair cells (OHCs) are involved in the cochlear amplification mechanism. Indeed, we found a strong morphological damage of the OHCs and the total absence of MOCs when Hoxb1 function was abolished in r41. A hypothesis is that MOC neuron endings could play a trophic function on OHCs and that the physical interaction between MOCs and OHCs is essential for proper maturation and functioning of OHCs2. In order to assess if the degeneration of OHCs and consequently altered hearing thresholds might be caused by the absence of synaptic/trophic stimulation of OHCs from the MOC fibers, we analyzed Hoxb1 mutant for the dorsal (sensory) and the ventral (motor) domain respectively. The sensory cochlear populations were affected in Hoxb1flox Atoh1-Cre and Hoxb1flox Ptf1a-Cre mice, whereas the olivocochlear motoneurons were deleted by using Hoxb1flox Nkx2.2-Cre mutants. The transmission and scanning electron microscopy’s study showed that the absence of Hoxb1 in sensory domain of r4 does not impair the proper development of OHCs, which maintain a regular morphology and fail to reproduce the severe phenotype observed in Hoxb1null mutants. On the other hand, our preliminary data on Hoxb1flox Nkx2.2-Cre mutants seem to highlight a key role for MOCs, which origin from this domain, on OHC survival and sound amplification