Chondrocyte Polarity During Endochondral Ossification Requires Protein-Protein Interactions Between Prickle1 and Dishevelled2/3.

The expansion and growth of the endochondral skeleton requires organized cell behaviors that control chondrocyte maturation and oriented division. In other organs, these processes are accomplished through Wnt/planar cell polarity (Wnt/PCP) signaling pathway and require the protein-protein interactions of core components including Prickle1 (PK1) and Dishevelled (DVL). To determine the function of Wnt/PCP signaling in endochondral ossification of the cranial base and limb, we utilized the Prickle1Beetlejuice (Pk1Bj ) mouse line. The Pk1Bj allele has a missense mutation in the PK1 LIM1 domain that results in a hypomorphic protein. Similar to human patients with Robinow syndrome, the Prickle1Bj/Bj mouse mutants lack growth plate expansion resulting in shorter limbs and midfacial hypoplasia. Within the Prickle1Bj/Bj limb and cranial base growth plates we observe precocious maturation of chondrocytes and stalling of terminal differentiation. Intriguingly, we observed that the growth plate chondrocytes have randomized polarity based on the location of the primary cilia and the location of PRICKLE1, DVL2, and DVL3 localization. Importantly, mutant PK1Bj protein has decreased protein-protein interactions with both DVL2 and DVL3 in chondrocytes as revealed by in vivo co-immunoprecipitation and proximity ligation assays. Finally, we propose a model where the interaction between the Prickle1 LIM1 domain and DVL2 and DVL3 contributes to chondrocyte polarity and contributes to proximal-distal outgrowth of endochondral elements. © 2021 American Society for Bone and Mineral Research (ASBMR).