| Neurotrophin-Trk signaling is essential for survival and target innervation of specific populations of neurons during development in the mammalian nervous system. However, the role of neurotrophins during maintenance of the adult nervous system is still unclear. To study the role of neurotrophin-Trk signaling during adulthood, I generated Trk knock-in alleles harboring a Phenylalanine (F) to Alanine (A) mutation that allows for pharmacological control of Trk kinase activity. Unlike Trk null mice which are perinatal lethal, homozygous TrkAF592A, TrkB F616A and TrkCF617A knock-in mice are viable and fertile with no observable phenotype. Yet, nanomolar concentrations of either 1NMPP1 or 1NaPP1, derivatives of the general kinase inhibitor PP1, inhibit NGF and BDNF signaling in TrkAF592A and TrkB F616A neurons, respectively, while no such Trk inhibition is observed in wild-type neurons. Moreover, oral administration of 1NMPP1 leads to specific inhibition of TrkAF592A, TrkBF616A and TrkC F167A signaling in vivo. Using these Trk F-A knock-in mice, I show that TrkA kinase activity is required for maintenance of target innervation of peptidergic sensory neurons, but not sympathetic neurons in adulthood. Regeneration of both peptidergic sensory neurons and sympathetic neurons, however, require TrkA activity. TrkB activity is required for maintenance of motor neuron terminals in adult mice as well. These findings indicate that neurotrophin-Trk signaling controls maintenance and regeneration of specific populations of neurons in the adult nervous system. |
