The research of the Unit on Molecular Genetics focuses on the development and function of the mammalian central nervous system, using the generation and study of mouse mutants as a major approach. The importance of mouse mutants to the study of mammalian development and function has two complementary aspects: First, mouse mutants lacking specific genes allow the testing of hypotheses about the roles of these genes. Second, mouse mutants with overt phenotypes can be studied to provide fundamental insights into biological processes. In this project we are testing specific hypotheses about the role of neuropeptides in development and adult function through a comprehensive mutational analysis of neuropeptide systems. Two classes of neuropeptides, somatostatin and the endogenous opioids, have been highly conserved during evolution, are expressed in early stages of embryogenesis, and function through similar families of G- protein coupled receptors. To investigate their roles in development and in adult function, we are systematically mutating the genes for somatostatin and its five receptors, and for the three endogenous opioid encoding genes and their receptors. While in each system the ligands may be regulatory, the receptors are structural components of the signal transduction pathways: the response of the system to the absence of each may be different, and informative. We have introduced a null allele at the somatostatin locus into the mouse germline; mice homozygous for the somatostatin null allele are viable. We are now analyzing these mice as well as introducing null alleles at the five different somatostatin receptor loci and at the endogenous opioid ligand and receptor loci. This systematic approach to the analysis of neuropeptide function will be essential in gaining new insights into the roles of these complex molecules.
