Abstract
Neurotrophic factors control a range of activities in developing neurons,
including survival, proliferation, migration and neuronal
differentiation. Two classes of neurotrophic factors that are strongly
linked to neuronal development of the peripheral nervous system are the
neurotrophins and GDNF family ligands. Like other trophic factors they
act by triggering signalling through receptor tyrosine kinases. This
thesis addresses novel functions for the receptor of GDNF family ligands
in peripheral nervous system development and how specificity is achieved
at different levels of the trophic factor signalling pathway.
In paper I, NT3, which has been considered to be a promiscuous
neurotrophin, is demonstrated to only signal through the TrkC receptor,
despite the presence of TrkB. In genetically modified mice, NT3/TrkC, but
not NT3/TrkB, could promote survival in the majority of cochleovestibular
neurons. Furthermore, NT3/TrkC could not substitute for BDNF/TrkB in
final target innervation of the vestibular system of the inner ear.
In paper II and III, Ret, the receptor for GDNF family ligands, is shown
to require the binding of the adaptor protein Frs2 to its phosphorylated
tyrosine 1062 for migration. In addition, phosphorylated tyrosine 981 was
also necessary for a full migratory response, showing cooperation between
these tyrosines. Moreover, the subcellular localization of Ret was
dependent on which adaptor that binds to tyrosine 1062, highlighting a
new function for adaptor proteins.
In paper IV we have ablated Ret in a subpopulation of nociceptive neurons
in vivo. We show that Ret was important for the proper expression of ion
channels and G protein-coupled receptors. The loss of Ret also led to
behavioural changes when mechanical and hot stimuli were applied to the
genetically modified mice. This demonstrates the necessity of Ret for
normal development of mechano- and thermosensation.
In conclusion this thesis contributes to the elucidation of how
specificity in neurotrophic factor signalling is achieved and the
definition of new roles for neurotrophic factors in development.
