Brain-derived neurotrophic factor and glial cell line-derived neurotrophicfactor are required simultaneously for survival of dopaminergic primary sensory neurons in vivo

Null mutations affecting members of the transforming growth factor-band neu rotrophin families result in overlapping patterns of neuronal cell death. T his is particularly striking in the cranial sensory nodose-petrosal ganglio n complex (NPG), in which loss of either glial cell line-derived neurotroph ic factor (GDNF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4 (NT-4) results in a 30-50% reduction in neuronal survival. It is unknown, however, whether GDNF and any single neurotrophin support survival of the same cells, and if so, whether they are required si multaneously or sequentially during development. To approach these issues w e defined survival requirements of nodose and petrosal neurons for GDNF in vitro and in bdnf, gdnf, and bdnf/gdnf null mutant mice, as well as the dis tribution of GDNF in NPG target tissues. Our analyses focused on the total population of ganglion cells as well as the subset of NPG neurons that are dopaminergic. Neuron losses in bdnf/gdnf double mutants are not additive of the losses in single bdnf or gdnf null mutants, indicating that many cells , including dopaminergic neurons, require both GDNF and BDNF for survival i n vivo. Moreover, both factors are required during the same period of devel opment, between embryonic day (E) 15.5 and E17.5. In addition, GDNF, like B DNF is expressed in target tissues at the time of initial target innervatio n and coincident with GDNF dependence of the innervating neurons. Together, these findings demonstrate that both GDNF and BDNF can act as target-deriv ed trophic factors and are required simultaneously for survival of some pri mary sensory neurons.