CELL CELL INTERACTIONS REQUIRED FOR SYNAPSE FORMATION

Neurological Disorders And Stroke

Investigators

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Abstract

We have been examining how sympathetic neurons chose the neurotransmitters that they will use and how target tissues acquire the appropriate complement of receptors and effector proteins. Descriptive studies delineated a developmental change in transmitter phenotype from noradrenergic to cholinergic in the sympathetic innervation of rodent sweat glands. Transplantation and culture experiments indicate that interactions with the target tissue, mediated by a secreted differentiation factor, induce this change. Studies are in progress to identify the sweat gland factor. By examining albino mice which lack tyrosine hydroxylase and catecholamines, we discovered that the early catecholaminergic innervation plays a critical role in triggering the onset of secretory responsiveness in developing glands. We have identified a second target of cholinergic sympathetic neurons, the periosteum. Analysis of the transmitter properties of the developing periosteal innervation coupled with transplantation studies indicate that these sympathetic neurons, like those that innervate sweat glands, undergo a target-directed transmitter switch. While innnervation of vasculature in limb skeletal muscle has been proposed as a third target of cholinergic sympathetic neurons, cholinergic markers are absent from the innervation of the muscle vasculature in rodents. We are also examining the trophic factor responsiveness of developing sympathetic neurons in vivo. All postmitotic sympathetic neurons require NGF for survival while half also require NT-3. Both NGF and NT-3 activate the tyrosine kinase receptor, trkA. This year we focussed on the role of the low affinity neurotrophin receptor (p75) in mediating NGF and NT-3 actions. Sympathetic neuron number is elevated postnatally in transgenic mice that lack p75 but is normal in adult p75 null mice. Cell culture studies had suggested that p75 can sharpen the specificity of trkA for NGF, decreasing the ability of NT-3 to activate it. Consistent with this notion, we found that mice that were heterozygous for an NT-3 deletion and lacked P75 had normal numbers of sympathetic neurons. Our data suggest that the principal role of the p75 receptor in sympathetic neurons is not to facilitate activation of trkA by NGF or to cause cell death but to sharpen the specificity of trkA for NGF.