Adenomatous polyposis coli-mediated control of beta-catenin is essential for both chondrogenic and osteogenic differentiation of skeletal precursors.
BACKGROUND
During skeletogenesis, protein levels of beta-catenin in the canonical Wnt signaling pathway determine lineage commitment of skeletal precursor cells to osteoblasts and chondrocytes. Adenomatous polyposis coli (Apc) is a key controller of beta-catenin turnover by down-regulating intracellular levels of beta-catenin.


RESULTS
To investigate whether Apc is involved in lineage commitment of skeletal precursor cells, we generated conditional knockout mice lacking functional Apc in Col2a1-expressing cells. In contrast to other models in which an oncogenic variant of beta-catenin was used, our approach resulted in the accumulation of wild type beta-catenin protein due to functional loss of Apc. Conditional homozygous Apc mutant mice died perinatally showing greatly impaired skeletogenesis. All endochondral bones were misshaped and lacked structural integrity. Lack of functional Apc resulted in a pleiotropic skeletal cell phenotype. The majority of the precursor cells lacking Apc failed to differentiate into chondrocytes or osteoblasts. However, skeletal precursor cells in the proximal ribs were able to escape the noxious effect of functional loss of Apc resulting in formation of highly active osteoblasts. Inactivation of Apc in chondrocytes was associated with dedifferentiation of these cells.


CONCLUSIONS
Our data indicate that a tight Apc-mediated control of beta-catenin levels is essential for differentiation of skeletal precursors as well as for the maintenance of a chondrocytic phenotype in a spatio-temporal regulated manner.
Miclea
Razvan L
RL
Department of Tissue Regeneration, Institute for Biomedical Technology, University of Twente, Enschede, The Netherlands. r.l.miclea@lumc.nl
Karperien
Marcel
M
Bosch
Cathy Aj
CA
van der Horst
Geertje
G
van der Valk
Martin A
MA
Kobayashi
Tatsuya
T
Kronenberg
Henry M
HM
Rawadi
Georges
G
Akçakaya
Pinar
P
Löwik
Clemens Wgm
CW
Fodde
Riccardo
R
Wit
Jan Maarten
JM
Robanus-Maandag
Els C
EC
D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D020219:Chondrogenesis / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics; D004622:Embryo, Mammalian / Q000196:embryology / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D013997:Time Factors; D051176:beta Catenin / Q000235:genetics*
D025601:Adenomatous Polyposis Coli Protein; C447413:Col2a1 protein, mouse; D024043:Collagen Type II; D051176:beta Catenin