P53 is required for the developmental restriction in Müller glial proliferation in mouse retina.
Müller glia are normally mitotically quiescent cells, but in certain pathological states they can re-enter the mitotic cell cycle. While several cell cycle regulators have been shown to be important in this process, a role for the tumor suppressor, p53, has not been demonstrated. Here, we investigated a role for p53 in limiting the ability of Müller glia to proliferate in the mature mouse retina. Our data demonstrate that Müller glia undergo a developmental restriction in their potential to proliferate. Retinal explants or dissociated cultures treated with EGF become mitotically quiescent by the end of the second postnatal week. In contrast, Müller glia from adult trp53-/+ or trp53-/- mice displayed a greater ability to proliferate in response to EGF stimulation in vitro. The enhanced proliferative ability of trp53 deficient mice correlates with a decreased expression of the mitotic inhibitor Cdkn1a/p21(cip) and an increase in c-myc, a transcription factor that promotes cell cycle progression. These data show that p53 plays an essential role in limiting the potential of Müller glia to re-enter the mitotic cycle as the retina matures during postnatal development.
Department of Biological Structure, University of Washington, Seattle, Washington, USA.
Yumi
Y
Ueki
Mike O
MO
Karl
Samuel
S
Sudar
Julia
J
Pollak
Russell J
RJ
Taylor
Kati
K
Loeffler
Matthew S
MS
Wilken
Sara
S
Reardon
Thomas A
TA
Reh
D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D051798:Inhibitor of Differentiation Protein 1 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009457:Neuroglia / Q000187:drug effects / Q000502:physiology*; D009924:Organ Culture Techniques; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics; D012160:Retina / Q000166:cytology* / Q000254:growth & development*; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
D051700:Activating Transcription Factor 3; D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004815:Epidermal Growth Factor; D005904:Glial Fibrillary Acidic Protein; D049452:Green Fluorescent Proteins; D017874:Immediate-Early Proteins; D051798:Inhibitor of Differentiation Protein 1; D012333:RNA, Messenger; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C103002:Atf3 protein, mouse; C489435:Btg2 protein, mouse; C493957:Cdkn1a protein, mouse; C489685:Hes5 protein, mouse; C497455:Idb1 protein, mouse