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Efficient Derivation of Retinal Pigment Epithelium Cells from Stem Cells
Published on: March 8, 2015
p27Kip1 and p57Kip2 regulate proliferation in distinct retinal progenitor cell populations
1Department of Genetics and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
In the developing vertebrate retina, progenitor cell proliferation must be precisely regulated to ensure appropriate formation of the mature tissue. Cyclin kinase inhibitors have been implicated as important regulators of proliferation during development by blocking the activity of cyclin-cyclin-dependent kinase complexes. We have found that the p27(Kip1) cyclin kinase inhibitor regulates progenitor cell proliferation throughout retinal histogenesis. p27(Kip1) is upregulated during the late G(2)/early G(1) phase of the cell cycle in retinal progenitor cells, where it interacts with the major retinal D-type cyclin-cyclin D1. Mice deficient for p27(Kip1) exhibited an increase in the proportion of mitotic cells throughout development as well as extensive apoptosis, particularly during the later stages of retinal histogenesis. Retroviral-mediated overexpression of p27(Kip1) in mitotic retinal progenitor cells led to premature cell cycle exit yet had no dramatic effects on Müller glial or bipolar cell fate specification as seen with the Xenopus cyclin kinase inhibitor, p27(Xic1). Consistent with the overexpression of p27(Kip1), mice lacking one or both alleles of p27(Kip1) maintained the same relative ratios of each major retinal cell type as their wild-type littermates. During the embryonic stages of development, when both p27(Kip1) and p57(Kip2) are expressed in retinal progenitor cells, they were found in distinct populations, demonstrating directly that different retinal progenitor cells are heterogeneous with respect to their expression of cell cycle regulators.
Insights
The p27(Kip1) cyclin kinase inhibitor regulates retinal progenitor cell proliferation and cell cycle exit during development. Mice lacking p27(Kip1) show increased cell division and apoptosis, yet retinal cell ratios remain consistent.
Area of Science:
- Developmental biology
- Cell cycle regulation
- Retinal histogenesis
Background:
- Precise regulation of progenitor cell proliferation is crucial for vertebrate retina development.
- Cyclin-dependent kinase inhibitors (CKIs) are key regulators of cell proliferation by inhibiting cyclin-CDK complexes.
Purpose of the Study:
- To investigate the role of the p27(Kip1) CKI in regulating progenitor cell proliferation during retinal development.
- To understand the cell cycle dynamics and cell fate implications of p27(Kip1) activity in the developing retina.
Main Methods:
- Analysis of p27(Kip1) expression during the cell cycle in retinal progenitor cells.
- Generation and analysis of p27(Kip1)-deficient mice.
- Retroviral-mediated overexpression of p27(Kip1) in retinal progenitor cells.
Main Results:
- p27(Kip1) is upregulated in late G(2)/early G(1) phase and interacts with cyclin D1 in retinal progenitor cells.
- p27(Kip1)-deficient mice display increased mitotic cells and apoptosis during retinal histogenesis.
- Overexpression of p27(Kip1) induces premature cell cycle exit without altering major retinal cell fate specification.
- p27(Kip1) and p57(Kip2) are expressed in distinct progenitor cell populations, indicating retinal progenitor cell heterogeneity.
Conclusions:
- p27(Kip1) is a critical regulator of progenitor cell proliferation and cell cycle exit in the developing vertebrate retina.
- Despite its role in cell cycle control, p27(Kip1) does not significantly alter the relative proportions of major retinal cell types.
- The developing retina exhibits cellular heterogeneity in the expression of cell cycle regulators like p27(Kip1) and p57(Kip2).
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