Background The automatic nervous system performs many functions that are abnormal in PWS: feeding, drinking, thermoregulation, intestinal motility, reproduction, reaction to stress and infection and together with the autonomic system of the brain, emotion and other complex behaviors. The cells (neurons) of the autonomic nervous system extend processes to other important organs such as the salivary glands and the intestine. The intestinal tract has its own nervous system, the enteric nervous system. Rationale. Necdin is one of the proteins deficient in PWS. Mice that were made to be missing necdin, have problems in the embryonic development of the brain, the spinal cord, and the neurons that sense pain and heat. We recently found defects in the movement and growth of some of the clusters of autonomic neurons that flank the spinal cord, and abnormal processes that fail to extend to the salivary glands in necdin-null mice. However, we have not sufficiently examined the autonomic nervous system in these mice to know the extent of the defects or how they arise. We propose that autonomic nervous system deficiencies in PWS occur during to prenatal development, cause problems in the autonomic nervous system in PWS children and adults, and happen because the necdin protein is not present when it is needed for the proper development of these neurons. Relevance Statement We will identify defects selected regions of the autonomic nervous system (the superior cervical ganglia, other sympathetic chain ganglia, the neuroendocrine cells of the adrenal medulla, the sympathetic innervation of target organs including the salivary glands and the intestinal tract, and enteric nervous system). We will find out whether the defects happen when the neurons are first formed, when they move from one place to another, or when they send processes out to other organs and glands. The trk and Ret neurotrophic signaling pathways are essential for the normal development of the autonomic nervous system. We will find out whether these pathways are altered because necdin is missing. Knowledge of the signaling pathways that are perturbed by loss of necdin will facilitate targeted therapeutic interventions useful for individuals with PWS.
Rachel Wevrick, Ph.D. Associate Professor, Department of Medical Genetics
University of Alberta, Canada