Bone growth is driven by cell proliferation and the subsequent hypertrophy of chondrocytes arranged in columns of discoid cells that resemble stacks of coins. However, the molecular mechanisms that direct column formation and the importance of columnar organization to bone morphogenesis are not known. Here,we show in chick that discoid proliferative chondrocytes orient the division plane to generate daughter cells that are initially displaced laterally and then intercalate into the column. Downregulation of frizzled (Fzd) signaling alters the dimensions of long bones and produces cell-autonomous changes in proliferative chondrocyte organization characterized by arbitrary division planes and altered cell stacking. These defects are phenocopied by disruption of noncanonical effector pathways but not by inhibitors of canonical Fzd signaling. These findings demonstrate that the regulation of cell polarity and cell arrangement by noncanonical Fzd signaling plays important roles in generating the unique morphological characteristics that shape individual cartilage elements.
We thank Linda Chee for generating retroviruses; Chen-Ming Chuong, Phillipa Francis-West, Matsuhiro Iwamoto, Carole LaBonne, Ray Keller, Randall Moon,Clifford Tabin and John Wallingford for plasmids; Hongmei Jiang for statistical analysis; and Molly Ahrens, Greg Beitel, Richard Carthew and Robert Holmgren for comments and discussion. This work was supported by funding from the Searle Leadership Fund of the Chicago Community Trust, the Alumnae of Northwestern University, the National Center for Research Resources(NCRR1C06RR015497-01), and the National Institutes of Health(NIAMSAR054857-01). The authors state that there are no conflicts of interest. Deposited in PMC for release after 12 months.
