The mechanistic/mammalian target of rapamycin (mTOR) regulates various cellular processes, in part through incorporation into distinct protein complexes. The mTOR complex 1 (mTORC1) contains the Raptor subunit, while mTORC2 specifically contains the Rictor subunit. Mouse genetic studies, including ours, have revealed a critical role for mTOR in skeletogenesis through its expression in undifferentiated mesenchymal cells. In addition, we have recently revealed that mTORC1 expression in chondrocytes is crucial for skeletogenesis. Recent work indicates that mTOR regulates cellular functions, depending on the context, through both complex-dependent (canonical pathway) and complex-independent roles (noncanonical pathway). Here, we determined that mTOR regulates skeletal development through the noncanonical pathway, as well as the canonical pathway, in a cell-type and context-specific manner. Inactivation of Mtor in undifferentiated mesenchymal cells or chondrocytes led to either severe hypoplasia in appendicular skeletons or a severe and generalized chondrodysplasia, respectively. Moreover, Rictor deletion in undifferentiated mesenchymal cells or chondrocytes led to mineralization defects in some skeletal components. Finally, we revealed that simultaneous deletion of Raptor and Rictor in undifferentiated mesenchymal cells recapitulated the appendicular skeletal phenotypes of Mtor deficiency, whereas chondrocyte-specific Raptor and Rictor double-mutants exhibited milder hypoplasia of appendicular and axial skeletons than those seen upon Mtor deletion. These findings indicate that mTOR regulates skeletal development mainly through the canonical pathway in undifferentiated mesenchymal cells, but at least in part through the noncanonical pathway in chondrocytes.

雷帕霉素（mTOR）的机械/哺乳动物靶标可调节多种细胞过程，部分是通过掺入不同的蛋白质复合物中来实现的。mTOR复合体1（mTORC1）包含Raptor亚基，而mTORC2具体包含Rictor亚基。包括我们在内的小鼠遗传学研究表明，mTOR通过在未分化的间充质细胞中表达而在骨骼生成中起关键作用。此外，我们最近发现软骨细胞中mTORC1的表达对于骨骼生成至关重要。最近的工作表明，mTOR根据情况通过复杂依赖的（规范途径）和非依赖复杂的角色（非经典途径）调节细胞功能。在这里，我们确定了mTOR通过非经典途径以及经典途径调节骨骼发育，以单元格类型和特定于上下文的方式。灭活未分化的间充质细胞或软骨细胞中的Mtor分别导致阑尾骨骼的严重发育不全或严重和全身性软骨发育不良。此外，未分化的间充质细胞或软骨细胞中Rictor的缺失导致某些骨骼成分的矿化缺陷。最后，我们揭示了在未分化的间充质细胞中同时缺失Raptor和Rictor可以概括出Mtor缺乏症的阑尾骨骼表型，而软骨细胞特异性Raptor和Rictor双突变体的阑尾和轴向骨骼发育不如Mtor所见。删除。这些发现表明，mTOR主要通过未分化的间充质细胞中的经典途径调节骨骼发育，但至少部分通过软骨细胞中的非经典途径调节骨骼发育。