Role of the ret proto-oncogene in the development of the enteric nervous system

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Immunohistochemical analysis with the anti-Ret antibody was performed to investigate the expression of the c-ret proto-oncogene product (c-Ret protein) in embryonic, and adult rat tissues. During embryogenesis, it was expressed at high levels in the enteric neuroblasts and the sympathetic ganglia. c-Ret positive cells appeared in the mesenchyme around the rofegut and the dorsal aorta at day 11.5 and formed the myeteric plexus of the whole embryonic gut and the sympathetic truck at later stages, respectively. In the enteric nervous system, c-Ret positive cells began to contact each other to form the myenteric ganglia and were arranged between the muscle layrs. After birth, these neurons continued to express the c-Ret protein at variable levels. These results suggested that the c-Ret protein might be involved in the development of the enteric and sympathetic nervous system.We introduced several mutations of the ret proto-oncogene found in the Hirchsprung's disease.ret cDNA with each mutation was transfected into NIH 3T3 cells, cell lines expressing the mutant Ret proteins were established. The Ret proteins were usually expressed as a mature glycosylated form of 170 kDa protein present on the cell surface and an immature glycosylated form of the 150 kDa Ret protein in the endoplasmic reticulum. Western blot analysis revealed that very little of the 170 kDa Ret protein was expressed in transfectants while expression of the 150 kDa Ret protein was not affected. This result suggested that the Hirschsprung mutations impair the transport of the Ret protein to the plasma membrane.