Trigeminal sensory neurons require extrinsic signals to switch neurotrophin dependence during the early stages of target field innervation

Sensory neurons of the embryonic mouse trigeminal ganglion are transiently supported by brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), and NT4/5 during the earliest stages of target field innervation before they become dependent on nerve growth factor (NGF) for survival. To determine whether the switch from BDNF/NT3/NT4/5 dependence to NGF dependence occurs autonomously in these neurons or whether extrinsic signals are required, we studied the survival of trigeminal neurons in vitro before, during, and after the switchover period. Trigeminal neurons cultured before they show any response to NGF survived with BDNF, NT3, or NT4/5 well beyond the switchover period. When these early neurons were switched from BDNF, NT3, or NT4/5 to NGF after various times in culture they died as rapidly as neuro-trophin-deprived neurons. Neurons that were switched from BDNF, NT3, or NT4/5 to NGF in cultures set up at stages throughout the switchover period exhibited an NGF survival response that improved with age. Moreover, the ability of NGF to promote long-term survival also increased with embryonic age. These results show that, unlike the onset of BDNF dependence, which is controlled by an intrinsic timing mechanism in early sensory neurons, the switch to NGF dependence relies on extrinsic signals acting on the neurons during the switchover period and that in vivo signals are also required for the maturation of the NGF survival response from a transient to a long-term response. Retinoic acid, which induces NGF dependence in early sympathetic neurons, was ineffective in promoting NGF dependence in early sensory neurons.