p57^Kip2 regulates progenitor cell proliferation and amacrine interneuron development in the mouse retina

A precise balance between proliferation and differentiation must be maintained during retinal development to obtain the correct proportion of each of the seven cell types found in the adult tissue. Cyclin kinase inhibitors can regulate cell cycle exit coincident with induction of differentiation programs during development. We have found that the p57^Kip2 cyclin kinase inhibitor is upregulated during G1/G0 in a subset of retinal progenitor cells exiting the cell cycle between embryonic day 14.5 and 16.5 of mouse development. Retroviral mediated overexpression of p57^Kip2 in embryonic retinal progenitor cells led to premature cell cycle exit. Retinae from mice lacking 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 cell types. Postnatally, p57^Kip2 was found to be expressed in a novel subpopulation of amacrine interneurons. At this stage, p57^Kip2 did not regulate proliferation. However, perhaps reflecting its role during this late stage of development, animals lacking p57^Kip2 showed an alteration in amacrine subpopulations. p57^Kip2 is the first gene to be implicated as a regulator 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 distinct role in neuronal differentiation.