9808565 HIGGINS Dendrites are the primary site of synapse formation in the nervous system, and so it is important to learn how the growth of these processes are regulated. During the previous period of support, Dr. Higgins found that bone morphogenetic proteins induce dendritic growth in several classes of neurons, including embryonic rat sympathetic, hippocampal and spinal motor neurons. The current project explores the possibility that leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), and related neuropoietic cytokines have an opposing activity, and that they function as negative regulators of dendritic growth. The study of such inhibitory factors is important because dendritic regression is widespread in the nervous system, having been seen in many regions of the developing brain and also in neurodegenerative disorders and after acute neural injury. CNTF promotes the survival of postnatal sympathetic neurons; yet, in the same population, it causes dendritic regression. If CNTF exerts a similar dendrite-retracting influence on motor and striatal neurons in vivo, this would be expected to interfere with synaptic function and compete with the influence of dendrite-promoting molecules such as bone morphogenetic proteins. CNTF appears to have a dominant negative influence on dendritic growth; i.e., it induces dendritic regression even in the presence of optimal concentrations of other dendrite-promoting factors. We need to know more about how a survival-promoting molecule can simultaneously adversely affect neural function. To further characterize the effects of neuropoietic cytokines, the planned studies will: a) characterize the receptors and signal transduction system mediating dendritic retraction; and b) determine whether CNTF and other neuropoietic cytokines also promote dendritic retraction in neurons from the central nervous system.
