REGULATION OF EXPRESSION AND FUNCTION OF NEUROPEPTIDES DURING DEVELOPMENT

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Neuropeptides have been shown to have trophic and mitogenic effects, and have been implicated to play a role in development. The objectives of this project are to study the developmental regulation of expression of two neuropeptide genes codina for the pro-opiomelanocortin (POMC) and the pro-(met)enkephalin family of peptides, and to investigate the role of these peptides in development, particularly in the central nervous system (CNS). Two model vertebrate systems: the frog (Xenopus laevis) and mouse were used. Initial studies focused on defining the temporal and spatial expression of POMC and (met)enkephalin peptides during development. In situ hybridization histochemistry revealed the first appearance of POMC mRNA in the mouse CNS in the region of the presumptive arcuate nucleus, at embryonic day 10-1/2 (E 10-1/2), and in the anterior lobe and intermediate lobe of the pituitary at E 12-1/2 and E 14-1/2 respectively. Immunocytochemical studies indicated that the POMC mRNA is translated at E 10-1/2; the neurons expressing POMC matured rapidly, forming arborizations and growth cones at this stage. The POMC system appears to be expressed before other peptidergic systems studied (LHRH, oxytocin, vasopressin). In the frog CNS, POMC and pro-(met)enkephalin mRNA were present in early tadpoles at stage 45. POMC neurons were observed in the preoptic nucleus, hypothalamus and tegmentum, whereas cells with (met)enkephalin mRNA were present in the telencephalic midbrain and brain stem areas. The early expression of POMC in the developing CNS suggests that this family of peptides may be important in neurogenesis. The frog pro-enkephalin gene including the 5' upstream regulatory region is cloned. Work is now in progress to identify the regulatory elements, a prerequisite to identifying the factors that trigger the activation of the gene during development.