Regulation of cyclin dependent kinase inhibitor proteins during neonatal cerebella development.

The cyclin dependent kinase holoenzymes (CDKs), composed of catalytic (cdk) and regulatory (cyclin) subunits, promote cellular proliferation and are inhibited by cyclin dependent kinase inhibitor proteins (CDKIs). The CDKIs include the Ink4 family (p15Ink4b, p16Ink4a, p18Ink4c, p19Ink4d) and the KIP family (p21Cip1 and p27Kip1). The sustained induction of p21 and p18 during myogenesis implicates these CDKI in maintaining cellular differentiation. Herein we examined the CDK (cyclin D1, cdk5) and CDKI expression profiles during the first 24 days of postnatal rat cerebella development. Cdk5 abundance increased and cyclin D1 decreased from day 9 through to adulthood. The CDKIs increased transiently during differentiation. p27 increased 20-fold between days 4 and 24, whereas p21 rose twofold between 6 to 11 days. p19, p18 and p16 increased approximately two- to threefold, falling to low levels in the adult. Immunostaining of cyclin D1 was localized in the external granular cells, whereas p27, was found primarily in the Purkinje cells. The period of maximal differentiation between days 9 to 13 was associated with a change in p21 and p16 staining from the external granular and Purkinje cells to a primarily Purkinje cell distribution. Protein-calorie malnutrition, which was previously shown to arrest rat cerebella development, reduced cyclin D1 kinase activity and p27 levels. However, p16 and p21 levels were unchanged. We conclude that the CDKIs are induced with distinct kinetics in specific cell types and respond differentially to growth factors during cerebella development, suggesting discrete roles for these proteins in normal cerebella development.