Development requirements of neurotrophins in the mammalian nervous system

Sammanfattning: The survival of the mammalian peripheral nervous system neurons has long been known to depend on neurotrophic factor support during the period of programmed cell death. In fact this was the original hypothesis, put forward after the discovery of the prototype, nerve growth factor (NGF). This hypothesis postulated the existence of limited amounts of neurotrophic factors in target areas of peripheral sensory neurons, which are originally generated in excess. Following differentiation and establishment of target contact the neurons acquire dependency for neurotrophic factors for their survival. Only the neurons that successfully compete survive, the remainder die. In addition to NGF, there are several other neurotrophic factors: brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT- 4). They share about 50% amino acid homology, and bind to a family of related tyrosine kinase receptors. NGF activates trkA, BDNF and NT-4, trkB, while NT-3 activates trkC. I have studied the importance of all these factors and their receptors during development in neurotrophin mutant mice. I began this study to increase our knowledge on the role of neurotrophins for neuronal survival in vivo. I have studied the developmental requirements of dorsal root, nodose-petrosal and trigeminal ganglia neurons for neurotrophins during intervals of embryonic mouse development through early postnatal ages in single or compound null mutant mice. Together the results point out that NT-3 is affecting the precursors of these sensory neurons prior to target innervation and programmed cell death. 1 further showed that this effect is mediated, at least in the dorsal root ganglion, by a local production of NT-3. Moreover and most importantly NT-3 seems crucial for the sensory precursors to exit the cell cycle in order to differentiate, and if denied NT-3, the precursors remain in the cell cycle and die. As for BDNF and NT-4, we have confirmed and extended the earlier observations by identifying their roles for sensory neurons survival in vivo. The data describe the cooperative effect of these neurotrophic factors and defines an order of action in vivo. Finally, we established an animal model for aminoglycoside hearing impairment and showed the protective effect of NT-3 against hearing impairment.