HIGH-LEVELS OF EXPRESSION OF THE TUMOR-SUPPRESSOR GENE APC DURING DEVELOPMENT OF THE RAT CENTRAL-NERVOUS-SYSTEM

The adenomatous polyposis coli (APC) gene is a tumor suppresser gene t hat is mutated in human familial adenomatous polyposis, an autosomal d ominant condition with predisposition to colorectal carcinoma and brai n tumors. Although tumor suppressor genes appear to play a general rol e in regulating cellular proliferation, the normal biological function of the APC gene product is unknown. In the present study, we cloned f ragments of the rat homolog of the APC gene and examined its tissue di stribution by Northern blot analysis. These studies demonstrated parti cularly high levels of APC mRNA in brain. To gain clues to the role of the APC gene in brain function, we examined the neuroanatomical distr ibution of APC mRNA using in situ hybridization. In the adult, promine nt expression of APC mRNA was observed in the olfactory bulb, hippocam pus, and cerebellum, with low levels of hybridization in other regions of adult rat brain. In contrast, during embryonic and early postnatal development (1-2 weeks), high levels of APC expression were found thr oughout the brain and then decreased to adult levels by 6 weeks after birth, except in the olfactory bulb where the high levels of APC mRNA found in development persist in the adult. During development of corte x, cerebellum, and retina, APC mRNA expression was particularly promin ent in layers containing newly formed postmitotic neurons, with lower levels observed in the proliferative zones where neurogenesis occurs. The high levels of APC expression from early neurogenesis until late s tages of neuronal maturation suggest that APC may contribute to suppre ssing neuronal proliferation during this period of intense growth.