Mutation of p107 exacerbates the consequences of Rb loss in embryonic tissues and causes cardiac and blood vessel defects.
The retinoblastoma tumor-suppressor protein, pRb, is a member of the pocket protein family that includes p107 and p130. These proteins have well-defined roles in regulating entry into and exit from the cell cycle and also have cell cycle-independent roles in facilitating differentiation. Here we investigate the overlap between pocket protein's function during embryonic development by using conditional mutant alleles to generate Rb;p107 double-mutant embryos (DKOs) that develop in the absence of placental defects. These DKOs die between e13.5 and e14.5, much earlier than either the conditional Rb or the germline p107 single mutants, which survive to birth or are largely viable, respectively. Analyses of the e13.5 DKOs shows that p107 mutation exacerbates the phenotypes resulting from pRb loss in the central nervous system and lens, but not in the peripheral nervous system. In addition, these embryos exhibit novel phenotypes, including increased proliferation of blood vessel endothelial cells, and heart defects, including double-outlet right ventricle (DORV). The DORV is caused, at least in part, by a defect in blood vessel endothelial cells and/or heart mesenchymal cells. These findings demonstrate novel, overlapping functions for pRb and p107 in numerous murine tissues.
Berman
Seth D
SD
David H. Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA.
West
Julie C
JC
Danielian
Paul S
PS
Caron
Alicia M
AM
Stone
James R
JR
Lees
Jacqueline A
JA
D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002490:Central Nervous System / Q000166:cytology / Q000378:metabolism; D004622:Embryo, Mammalian / Q000098:blood supply / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006331:Heart Diseases / Q000196:embryology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007908:Lens, Crystalline / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D009154:Mutation; D016160:Retinoblastoma Protein / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D050720:Retinoblastoma-Like Protein p107 / Q000172:deficiency / Q000235:genetics*
D016160:Retinoblastoma Protein; D050720:Retinoblastoma-Like Protein p107
Nature. 2003 Jul 10;424(6945):223-8
12853964
Nat Rev Cancer. 2008 Oct;8(10):769-81
18800074
Proc Natl Acad Sci U S A. 2003 May 27;100(11):6546-51
12732721
Oncogene. 1997 Apr 17;14(15):1789-97
9150384
Dev Biol. 2001 Feb 15;230(2):230-42
11161575
Genes Dev. 1996 Jul 1;10(13):1633-44
8682294
J Med Genet. 2008 Aug;45(8):481-97
18456715
Proc Natl Acad Sci U S A. 2006 May 9;103(19):7345-50
16648263
Cell Mol Life Sci. 2006 Apr;63(7-8):767-80
16465443
Genes Dev. 2000 Dec 1;14(23):3037-50
11114892
Nature. 1992 Sep 24;359(6393):295-300
1406933
Oncogene. 2005 Apr 18;24(17):2810-26
15838517
EMBO J. 2005 May 4;24(9):1750-61
15861132
Genesis. 2000 Feb;26(2):113-5
10686601
Circ Res. 2004 Sep 3;95(5):459-70
15345668
EMBO J. 1996 Nov 15;15(22):6178-88
8947040
Mol Cell Biol. 2005 Mar;25(6):2486-97
15743840
Am J Med. 2002 Nov;113(7):580-6
12459405
Mol Cancer Res. 2008 Sep;6(9):1440-51
18819932
BMC Dev Biol. 2007 Jan 26;7:6
17257418
Genes Dev. 2004 Dec 1;18(23):2952-62
15574596
Genes Dev. 1996 Jul 1;10(13):1621-32
8682293
J Exp Med. 2001 Mar 19;193(6):741-54
11257140