Chondrocyte Polarity During Endochondral Ossification Requires Protein-Protein Interactions Between Prickle1 and Dishevelled2/3.
Chondrocyte Polarity During Endochondral Ossification Requires Protein-Protein Interactions Between Prickle1 and Dishevelled2/3.
复制标题
软骨内骨化过程中软骨细胞的极性需要 Prickle1 和 Dishevelled2/3 之间的蛋白质-蛋白质相互作用。
DOI：
10.1002/jbmr.4428
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Szabo-Rogers,HeatherL
中科院分区：
文献类型：
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作者：
Wan,Yong;Szabo-Rogers,HeatherL
软骨内骨骼的扩张和生长需要控制软骨细胞成熟和定向分裂的有组织的细胞行为。在其他器官中，这些过程是通过Wnt/平面细胞极性（Wnt/PCP）信号通路完成的，并且需要核心组分包括Prickle 1（PK 1）和Dishevelled（DVL）的蛋白质-蛋白质相互作用。为了确定Wnt/PCP信号传导在颅底和四肢的软骨内骨化中的功能，我们利用了Prickle 1Beetlejuice（Pk 1Bj）小鼠系。Pk 1Bj等位基因在PK 1 LIM 1结构域中具有错义突变，导致亚型蛋白。与Robinow综合征的人类患者相似，Prickle 1Bj/Bj小鼠突变体缺乏生长板扩张，导致四肢变短和面中部发育不全。在Prickle 1Bj/Bj肢体和颅底生长板内，我们观察到软骨细胞早熟成熟和终末分化停滞。有趣的是，我们观察到生长板软骨细胞具有基于初级纤毛的位置和PRICKLE 1、DVL 2和DVL 3定位的随机极性。重要的是，突变体PK 1Bj蛋白与软骨细胞中DVL 2和DVL 3的蛋白质-蛋白质相互作用降低，如体内免疫共沉淀和邻近连接测定所揭示的。最后，我们提出了一个模型，其中Prickle 1 LIM 1结构域与DVL 2和DVL 3之间的相互作用有助于软骨细胞的极性，并有助于近端-远端的软骨内分泌元件的生长。© 2021美国骨与矿物质研究学会（ASBMR）。
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 Pk1Bjallele has a missense mutation in the PK1 LIM1 domain that results in a hypomorphic protein. Similar to human patients with Robinow syndrome, the Prickle1Bj/Bjmouse mutants lack growth plate expansion resulting in shorter limbs and midfacial hypoplasia. Within the Prickle1Bj/Bjlimb 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 PK1Bjprotein 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).