p57(Kip2) regulates progenitor cell proliferation and amacrine interneurondevelopment in the mouse retina

A precise balance between proliferation and differentiation must be maintai ned during retinal development to obtain the correct proportion of each of the seven cell types found in the adult tissue. Cyclin kinase inhibitors ta n regulate cell cycle exit coincident with induction of differentiation pro grams during development. We have found that the p57(Kip2) cyclin kinase in hibitor is upregulated during G(1)/G(0) in a subset of retinal progenitor c ells exiting the cell cycle between embryonic day 14.5 and 16.5 of mouse de velopment. Retroviral mediated overexpression of p57(Kip2) in embryonic ret inal progenitor cells led to premature cell cycle exit. Retinae from mice l acking p57(Kip2) exhibited inappropriate S-phase entry and apoptotic nuclei were found in the region where p57(Kip2) is normally expressed. Apoptosis precisely compensated for the inappropriate proliferation in the p57(Kip2)- deficient retinae to preserve the correct proportion of the major retinal c ell types. Postnatally, p57(Kip2) was found to be expressed in a novel subp opulation of amacrine interneurons, At this stage, p57(Kip2) did not regula te proliferation. However, perhaps reflecting its role during this late sta ge of development, animals lacking p57(Kip2) showed an alteration in amacri ne subpopulations. p57(Kip2) is the first gene to be implicated as a regula tor of amacrine subtype/subpopulation development. Consequently, we propose that p57(Kip2) has two roles during retinal development, acting first as a cyclin kinase inhibitor in mitotic progenitor cells, and then playing a di stinct role in neuronal differentiation.