REDUCED CYCLIN D1 EXPRESSION IN THE CEREBELLA OF NUTRITIONALLY DEPRIVED RATS CORRELATES WITH DEVELOPMENTAL DELAY AND DECREASED CELLULAR DNA-SYNTHESIS

Nutritional deprivation in the early postnatal period severely inhibit s cerebellar growth and development, which is related in part to reduc ed levels of growth factors. Cyclin D1 encodes a growth factor-inducib le regulatory subunit of a serine/threonine kinase that is capable of phosphorylating the tumor suppressor pRB, thereby allowing normal prog ression through the G(1) phase of the cell-cycle. Because the abundanc e of cyclin D1 is rate limiting in this progression, we examined the r egulation of cyclin D1 expression in vivo, using a model of nutritiona l deprivation. Cyclin D1 expression in cerebella of fed control rats w as detected in the external granular layer and was associated with cel lular proliferation within this layer. Nutritional deprivation of rats reduced cerebellar weight, as well as the thickness of the molecular layer that largely consists of cells migrating from the external granu lar layer. Refeeding partially restored cerebellar weight, molecular l ayer thickness and increased external granular layer cyclin D1 immunos taining. Since nutritional deprivation is accompanied by lower levels of circulating insulin-like growth factor-I (IGF-I), we determined whe ther IGF-I directly stimulated the cyclin D1 promoter. The human cycli n D1 promoter linked to the luciferase reporter gene was stably integr ated into PC12 cells. IGF-I stimulated cyclin D1 promoter activity 4- to 6-fold at 6 hours (h). These findings are consistent with the notio n that nutritional deprivation may affect proliferative growth by alte ring expression of cyclin D1 in the germinal cell layer and that regul ation of cyclin D1 expression by growth factors may contribute to norm al neonatal cerebellar development. The reduction in cyclin D1 express ion as cells differentiate in the cerebellum is consistent with a pote ntial role for cyclin D1 in this process.