Making and breaking the innervation of the ear: neurotrophic support during ear development and its clinical implications

Analyses of single and double mutants of members of the neurotrophin family and their receptors are reviewed. These data demonstrate that the two neur otrophins, brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT- 3), and their high-affinity receptors trkB and trkC, are the sole support f or the developing afferent innervation of the ear. Neurotrophins are first expressed in the otocyst around the time afferent sensory neurons become po stmitotic. They are crucial for the survival of certain topologically disti nct populations of sensory neurons. BDNF supports all sensory neurons to th e semicircular canals, most sensory neurons to the saccule and utricle, and many sensory neurons to the apex and middle turn of the cochlea. In contra st, NT-3 supports few sensory neurons to the utricle and saccule, all senso ry neurons to the basal turn of the cochlea and most sensory neurons to the middle and apical turn. Some topologically restricted effects reflect the pattern of neurotrophin distribution as revealed by in situ hybridization ( e.g., loss of all innervation to the semicircular canal sensory epithelia i n BDNF or trkB mutants). However, other topologically restricted effects ca nnot be explained on the basis of current knowledge of neurotrophin or neur otrophin receptor distribution. Data on mutants also support the notion tha t BDNF may play a role in neonatal plastic reorganization of the pattern of innervation in the ear and possibly the brainstem. In contrast, data obtai ned thus far on the ability of neurotrophins to rescue adult sensory neuron after insults to cochlear hair cells are less compelling. The ear is a mod el system to test the interactions of the two neurotrophins, BDNF and NT-3, with their two high-affinity receptors, trkB and trkC.