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 (CDKI s). The CDKIs include the Ink4 family (p15(Ink4b) p16(Ink4a), p18(Ink4 c), p19(Ink4d)) and the KIP family (p21(Cip1) and p27(Kip1)). The sust ained 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 increas ed transiently during differentiation. p27 increased 20-fold between d ays 4 and 24, whereas p21 rose twofold between 6 to 11 days. p19, p18 and p16 increased approximately two- to threefold, falling to low leve ls in the adult. Immunostaining of cyclin D1 was localized in the exte rnal 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 gra nular and Purkinje cells to a primarily Purkinje cell distribution. Pr otein-calorie malnutrition, which was previously shown to arrest rat c erebella development, reduced cyclin D1 kinase activity and p27 levels . However, p16 and p21 levels were unchanged. We conclude that the CDK Is are induced with distinct kinetics in specific cell types and respo nd differentially to growth factors during cerebella development, sugg esting discrete roles for these proteins in normal cerebella developme nt. (C) 1998 Elsevier Science B.V. All rights reserved.