Cooperation between p27 and p107 during endochondral ossification suggests a genetic pathway controlled by p27 and p130.
Pocket proteins and cyclin-dependent kinase (CDK) inhibitors negatively regulate cell proliferation and can promote differentiation. However, which members of these gene families, which cell type they interact in, and what they do to promote differentiation in that cell type during mouse development are largely unknown. To identify the cell types in which p107 and p27 interact, we generated compound mutant mice. These mice were null for p107 and had a deletion in p27 that prevented its binding to cyclin-CDK complexes. Although a fraction of these animals survived into adulthood and looked similar to single p27 mutant mice, a larger number of animals died at birth or within a few weeks thereafter. These animals displayed defects in chondrocyte maturation and endochondral bone formation. Proliferation of chondrocytes was increased, and ectopic ossification was observed. Uncommitted mouse embryo fibroblasts could be induced into the chondrocytic lineage ex vivo, but these cells failed to mature normally. These results demonstrate that p27 carries out overlapping functions with p107 in controlling cell cycle exit during chondrocyte maturation. The phenotypic similarities between p107(-/-) p27(D51/D51) and p107(-/-) p130(-/-) mice and the cells derived from them suggest that p27 and p130 act in an analogous pathway during chondrocyte maturation.
Yeh
Nancy
N
Sloan-Kettering Institute, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Miller
Jeffrey P
JP
Gaur
Tripti
T
Capellini
Terence D
TD
Nikolich-Zugich
Janko
J
de la Hoz
Carmen
C
Selleri
Licia
L
Bromage
Timothy G
TG
van Wijnen
Andre J
AJ
Stein
Gary S
GS
Lian
Jane B
JB
Vidal
Anxo
A
Koff
Andrew
A
D000818:Animals; D000831:Animals, Newborn; D001835:Body Weight; D001842:Bone and Bones / Q000033:anatomy & histology; D018797:Cell Cycle Proteins / Q000378:metabolism; D049109:Cell Proliferation; D019902:Chondrocytes / Q000166:cytology; D020219:Chondrogenesis; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000172:deficiency / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D008297:Male; D051379:Mice; D009929:Organ Size; D010012:Osteogenesis / Q000235:genetics*; D010641:Phenotype; D050720:Retinoblastoma-Like Protein p107 / Q000172:deficiency / Q000378:metabolism*; D050717:Retinoblastoma-Like Protein p130 / Q000378:metabolism*; D016196:S Phase; D016019:Survival Analysis
D018797:Cell Cycle Proteins; D050720:Retinoblastoma-Like Protein p107; D050717:Retinoblastoma-Like Protein p130; D050760:Cyclin-Dependent Kinase Inhibitor p27