The mechanistic/mammalian target of rapamycin complex-1(mTORC1) orchestrates various signaling pathways and controls different cellular functions. Tuberous sclerosis complex 1 (Tsc1) and complex 2 (Tsc2) negatively regulate mTORC1 activity. Mouse genetic studies, including our own work, have demonstrated that inactivation of mTORC1 in undifferentiated mesenchymal cells and chondrocytes causes drastic skeletal abnormalities. Here we revealed that sustained overactivation of mTORC1 leads to abnormal skeletogenesis through its expression in undifferentiated mesenchymal cells during embryogenesis. Disruption of Tsc1 in undifferentiated mesenchymal cells by paired-related homeobox 1 (Prx1)-Cre-mediated recombination causes skeletal defects in appendicular skeletons. Meanwhile, inactivation of Tsc1 in chondrocytes via collagen type Ⅱ α1 (Col2a1)-Cre or in osteoprogenitors via Osterix (Osx)-Cre did not lead to skeletal abnormalities in either appendicular or axial skeletons. These findings provide a better insight into the molecular mechanism of skeletal development at the embryonic stage.