The cyclin-dependent kinase inhibitor p57Kip2 regulates cell cycle exit, differentiation, and migration of embryonic cerebral cortical precursors.
Mounting evidence indicates cyclin-dependent kinase (CDK) inhibitors (CKIs) of the Cip/Kip family, including p57(Kip2) and p27(Kip1), control not only cell cycle exit but also corticogenesis. Nevertheless, distinct activities of p57(Kip2) remain poorly defined. Using in vivo and culture approaches, we show p57(Kip2) overexpression at E14.5-15.5 elicits precursor cell cycle exit, promotes transition from proliferation to neuronal differentiation, and enhances process outgrowth, while opposite effects occur in p57(Kip2)-deficient precursors. Studies at later ages indicate p57(Kip2) overexpression also induces precocious glial differentiation, suggesting stage-dependent effects. In embryonic cortex, p57(Kip2) overexpression advances cell radial migration and alters postnatal laminar positioning. While both CKIs induce differentiation, p57(Kip2) was twice as effective as p27(Kip1) in inducing neuronal differentiation and was not permissive to astrogliogenic effects of ciliary neurotrophic factor, suggesting that the CKIs differentially modulate cell fate decisions. At molecular levels, although highly conserved N-terminal regions of both CKIs elicit cycle withdrawal and differentiation, the C-terminal region of p57(Kip2) alone inhibits in vivo migration. Furthermore, p57(Kip2) effects on neurogenesis and gliogenesis require the N-terminal cyclin/CDK binding/inhibitory domains, while previous p27(Kip1) studies report cell cycle-independent functions. These observations suggest p57(Kip2) coordinates multiple stages of corticogenesis and exhibits distinct and common activities compared with related family member p27(Kip1).
Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA. turyanna@hotmail.com
Anna
A
Tury
Georges
G
Mairet-Coello
Emanuel
E
DiCicco-Bloom
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002464:Cell Migration Inhibition / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D050761:Cyclin-Dependent Kinase Inhibitor p57 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000166:cytology / Q000201:enzymology*; D055495:Neurogenesis / Q000502:physiology*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley
C493961:Cdkn1b protein, mouse; C493965:Cdkn1c protein, mouse; D050761:Cyclin-Dependent Kinase Inhibitor p57; D050760:Cyclin-Dependent Kinase Inhibitor p27
Lab Invest. 2005 Mar;85(3):364-75
15696192
Cell. 2001 Feb 9;104(3):365-76
11239394
Nature. 1997 May 8;387(6629):151-8
9144284
Cell. 1996 May 31;85(5):733-44
8646781
Development. 2002 May;129(9):2087-98
11959819
J Biol Chem. 2007 Jan 5;282(1):390-6
17092932
Cell. 2005 Jul 15;122(1):119-31
16009138
Prog Neurobiol. 2004 Feb;72(3):183-93
15130709
Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1392-7
9465025
J Neurosci. 2007 Jun 6;27(23):6185-96
17553990
Mol Cell Neurosci. 2004 Mar;25(3):480-92
15033176
J Comp Neurol. 2001 Jan 22;429(4):601-14
11135238
J Cell Sci. 2001 Apr;114(Pt 7):1253-63
11256992
J Neurosci. 2002 Mar 1;22(5):1583-91
11880488
Science. 1991 Oct 11;254(5029):282-5
1925583
Genes Dev. 2006 Jun 1;20(11):1511-24
16705040
Cell. 1999 Nov 24;99(5):499-510
10589678
J Neurosci. 2005 May 18;25(20):4917-29
15901773
Glia. 2002 Feb;37(2):93-104
11754208
Science. 1997 Oct 17;278(5337):477-83
9334309
Nat Rev Neurosci. 2002 Sep;3(9):694-704
12209118
Nat Cell Biol. 2006 Jan;8(1):17-26
16341208
Cell. 1996 May 31;85(5):707-20
8646779
Oncogene. 1997 Nov 20;15(21):2541-51
9399642
Neuron. 2007 May 3;54(3):357-69
17481390
Cell Cycle. 2008 Sep 15;7(18):2781-6
18769142
Cell Growth Differ. 2001 Aug;12(8):387-96
11504704
Neural Dev. 2009 Jan 05;4:1
19123928
Development. 2000 Aug;127(16):3593-605
10903183
Genes Dev. 2004 Apr 15;18(8):862-76
15078817
J Neurosci. 2009 Jan 21;29(3):775-88
19158303
Genes Dev. 1999 Jun 15;13(12):1501-12
10385618
Bioessays. 1998 Dec;20(12):1020-9
10048302
Histochem Cell Biol. 2007 Feb;127(2):195-203
17024454
Neuron. 2005 Oct 6;48(1):45-62
16202708
EMBO J. 1997 Jan 15;16(2):306-17
9029151
J Neurochem. 2008 Aug;106(4):1681-98
18564368
Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1319-24
16432194
Nat Neurosci. 2004 Mar;7(3):229-35
14770186
Curr Opin Neurobiol. 2001 Feb;11(1):66-73
11179874
J Biol Chem. 2003 Dec 26;278(52):52919-23
14530263
J Biol Chem. 1997 Jan 3;272(1):442-7
8995281
Nature. 1961 Nov 25;192:766-8
17533671
Proc Natl Acad Sci U S A. 2003 Dec 23;100(26):15619-24
14671317
Genes Dev. 1997 Sep 15;11(18):2335-46
9308962
EMBO Rep. 2001 Jan;2(1):27-34
11252720
Science. 1974 Feb 1;183(4123):425-7
4203022
J Comp Neurol. 1998 Jul 27;397(2):181-98
9658283
Dev Neurosci. 2004 Mar-Aug;26(2-4):197-207
15711060
Dev Cell. 2008 Feb;14(2):159-69
18267085
J Cell Biol. 2002 Jul 22;158(2):321-9
12119358
Proc Natl Acad Sci U S A. 1997 Apr 1;94(7):3357-62
9096398
J Biol Chem. 2005 Apr 1;280(13):12896-901
15695523