Abstract
BackgroundCyclin-dependent kinase (CDK) inhibitors play an important role in regulating cell cycle progression, cell cycle exit and cell differentiation. p27KIP1 (p27), one of the major CDK inhibitors in the retina, has been shown to control the timing of cell cycle exit of retinal progenitors. However, the precise role of this protein in retinal development remains largely unexplored. We thus analyzed p27-deficient mice to characterize the effects of p27 loss on proliferation, differentiation, and survival of retinal cells.MethodsExpression of p27 in the developing and mature mouse retina was analyzed by immunohistochemistry using antibodies against p27 and cell type-specific markers. Cell proliferation and differentiation were examined in the wild-type and p27-deficient retinas by immunohistochemistry using various cell cycle and differentiation markers.ResultsAll postmitotic retinal cell types expressed p27 in the mouse retinas. p27 loss caused extension of the period of proliferation in the developing retinas. This extra proliferation was mainly due to ectopic cell cycle reentry of differentiating cells including bipolar cells, Müller glial cells and cones, rather than persistent division of progenitors as previously suggested. Aberrant cell cycle activity of cones was followed by cone death resulting in a significant reduction in cone number in the mature p27-deficient retinas.ConclusionsAlthough expressed in all retinal cell types, p27 is required to maintain the quiescence of specific cell types including bipolar cells, Müller glia, and cones while it is dispensable for preventing cell cycle reentry in other cell types.
Highlights
Cyclin-dependent kinase (CDK) inhibitors play an important role in regulating cell cycle progression, cell cycle exit and cell differentiation. p27KIP1 (p27), one of the major cyclin-dependent kinases (CDKs) inhibitors in the retina, has been shown to control the timing of cell cycle exit of retinal progenitors
The activity of cyclin/CDK complexes is regulated by CDK inhibitors, which inhibit cell cycle progression and promote cell cycle exit [1, 2]
At postnatal day 0 (P0), p27 immunoreactivity was observed in the ganglion cell layer (GCL), the inner part of the neuroblastic layer (NBL) containing amacrine cells, and the outer portion of the NBL containing differentiating photoreceptors (Fig. 1a). p27 was detected in most, if not all, cells in the central retina at P6 (Fig. 1a)
Summary
Cyclin-dependent kinase (CDK) inhibitors play an important role in regulating cell cycle progression, cell cycle exit and cell differentiation. p27KIP1 (p27), one of the major CDK inhibitors in the retina, has been shown to control the timing of cell cycle exit of retinal progenitors. Cyclin-dependent kinase (CDK) inhibitors play an important role in regulating cell cycle progression, cell cycle exit and cell differentiation. P27KIP1 (p27), one of the major CDK inhibitors in the retina, has been shown to control the timing of cell cycle exit of retinal progenitors. During development of the CNS, precise coordination of progenitor cell proliferation and cell cycle exit is essential for generation of appropriate number of neurons. The activity of cyclin/CDK complexes is regulated by CDK inhibitors, which inhibit cell cycle progression and promote cell cycle exit [1, 2]. CDK inhibitors have equivalent roles in vivo in the context of CNS development or whether they function in a cell type-specific manner remain largely unexplored. Multipotent retinal progenitors divide extensively during development and lose proliferative capacity as they withdraw from the cell cycle and differentiate into specific cell types. In the Xenopus retina, p27 inhibits the cell cycle and promotes the cell fate of Müller
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