p27(Kip1) regulates cell cycle withdrawal of late multipotent progenitor cells in the mammalian retina

The cyclin-dependent kinase inhibitor protein, p27(Kip1), is necessary for the timing of cell cycle withdrawal that precedes terminal differentiation in oligodendrocytes of the optic nerve. Although p27(Kip1) is widely expres sed in the developing central nervous system, it is not known whether this protein has a similar role in neuronal differentiation. To address this iss ue, we have examined the expression and function of p27(Kip1) in the develo ping retina, a well-characterized part of the central nervous system. p27(K ip1) is expressed in a pattern coincident with the onset of differentiation of most retinal cell types. In vitro analyses show that p27(Kip1) accumula tion in retinal cells correlates with cell cycle withdrawal and differentia tion, and when overexpressed, p27(Kip1) inhibits proliferation of the proge nitor cells. Furthermore, the histogenesis of photoreceptors and Muller gli a is extended in the retina of p27(Kip1)-deficient mice. Finally, we examin ed the adult retinal dysplasia in p27(Kip1)-deficient mice with cell-type-s pecific markers. Contrary to previous suggestions that the dysplasia is cau sed by excess production of photoreceptors, we suggest that the dysplasia i s due to the displacement of reactive Muller glia into the layer of photore ceptor outer segments. These results demonstrate that p27(Kip1) is part of the molecular mechanism that controls the decision of multipotent central n ervous system progenitors to withdraw from the cell cycle. Second, postmito tic Muller glia have a novel and intrinsic requirement for p27(Kip1) in mai ntaining their differentiated state. (C) 2000 Academic Press.