Background. The autonomic nervous system (ANS) performs functions that are abnormal in PWS: feeding, drinking, thermoregulation, intestinal motility, reproduction, reaction to stress and infection, and together with the ANS of the brain, emotion and other complex behaviors. The cells (neurons) of the ANS communicate with important organs such as the pancreas and the intestine.
Rationale. Necdin is one of the proteins missing in PWS. Mice 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 ANS in these mice to know the extent of the defects or how they arise. We propose that ANS deficiencies in PWS occur during to prenatal development, cause problems in the ANS 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. We will identify defects selected regions of the ANS (the superior cervical ganglia, other sympathetic chain ganglia, the neuroendocrine cells of the adrenal medulla, the sympathetic innervation of target organs including the pancreas, heart and the intestinal tract, and the hypothalamus and brainstem). 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 communicate with other organs and glands. The Trk neurotrophic signaling pathway is essential for the normal development of the ANS. Knowledge of the signaling pathways that are perturbed by loss of necdin will facilitate targeted therapeutic interventions useful for individuals with PWS.