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首页> 外文期刊>PLoS Genetics >Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis
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Kinesin-1 promotes chondrocyte maintenance during skeletal morphogenesis

机译：Kinesin-1促进骨骼形态发生过程中的软骨细胞维持

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During skeletal morphogenesis diverse mechanisms are used to support bone formation. This can be seen in the bones that require a cartilage template for their development. In mammals the cartilage template is removed, but in zebrafish the cartilage template persists and the bone mineralizes around the cartilage scaffold. Remodeling of unmineralized cartilage occurs via planar cell polarity (PCP) mediated cell rearrangements that contribute to lengthening of elements; however, the mechanisms that maintain the chondrocyte template that supports perichondral ossification remain unclear. We report double mutants disrupting two zebrafish kinesin-I genes (hereafter kif5Blof) that we generated using CRISPR/Cas9 mutagenesis. We show that zygotic Kif5Bs have a conserved function in maintaining muscle integrity, and are required for cartilage remodeling and maintenance during craniofacial morphogenesis by a PCP-distinct mechanism. Further, kif5Blof does not activate ER stress response genes, but instead disrupts lysosomal function, matrix secretion, and causes deregulated autophagic markers and eventual chondrocyte apoptosis. Ultrastructural and transplantation analysis reveal neighboring cells engulfing extruded kif5Blof chondrocytes. Initial cartilage specification is intact; however, during remodeling, kif5Blof chondrocytes die and the cartilage matrix devoid of hypertrophic chondrocytes remains and impedes normal ossification. Chimeric and mosaic analyses indicate that Kif5B functions cell-autonomously in secretion, nuclear position, cell elongation and maintenance of hypertrophic chondrocytes. Interestingly, large groups of wild-type cells can support elongation of neighboring mutant cells. Finally, mosaic expression of kif5Ba, but not kif5Aa in cartilage rescues the chondrocyte phenotype, further supporting a specific requirement for Kif5B. Cumulatively, we show essential Kif5B functions in promoting cartilage remodeling and chondrocyte maintenance during zebrafish craniofacial morphogenesis.
机译：在骨骼形态发生过程中，多种机制被用来支持骨形成。可以在需要软骨模板进行发育的骨骼中看到这一点。在哺乳动物中，去除了软骨模板，但是在斑马鱼中，软骨模板持续存在并且骨头在软骨支架周围矿化。未矿化软骨的重塑是通过平面细胞极性（PCP）介导的细胞重排而发生的，从而导致元素延长。然而，维持软骨细胞模板支持软骨周围骨化的机制仍不清楚。我们报道了双重突变体破坏了我们使用CRISPR / Cas9诱变产生的两个斑马鱼驱动蛋白-I基因（以下称为kif5Blof）。我们显示，合子Kif5Bs在保持肌肉完整性方面具有保守的功能，并且在颅面部形态发生过程中通过PCP独特的机制进行软骨重塑和维持是必需的。此外，kif5Blof不会激活ER应激反应基因，而是会破坏溶酶体功能，基质分泌，并导致失调的自噬标记和最终的软骨细胞凋亡。超微结构和移植分析显示，周围的细胞吞噬了挤出的kif5Blof软骨细胞。初始软骨规格完好无损;然而，在重塑过程中，kif5Blof软骨细胞死亡，缺乏肥大软骨细胞的软骨基质仍然存在，并阻碍了正常的骨化。嵌合和镶嵌分析表明，Kif5B在分泌，核位置，细胞伸长和肥大软骨细胞维持方面具有细胞自主功能。有趣的是，大批野生型细胞可以支持相邻突变细胞的延长。最后，在软骨中表达kif5Ba而不表达kif5Aa可以拯救软骨细胞表型，进一步支持了对Kif5B的特殊要求。累计地，我们显示出必要的Kif5B功能在斑马鱼颅面形态发生过程中促进软骨重塑和软骨细胞维持。

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