Despite its central position in oncogenic intracellular signaling networks, the role of mTORC1 in epithelial development has not been studied extensively in vivo. Here, we have used the epidermis as a model system to elucidate the cellular effects and signaling feedback sequelae of mTORC1 loss of function in epithelial tissue. In mice with conditional epidermal loss of the mTORC1 components Rheb or Rptor, mTORC1 loss of function unexpectedly resulted in a profound skin barrier defect with epidermal abrasions, blistering, and early postnatal lethality, due to a thinned epidermis with decreased desmosomal protein expression and incomplete biochemical differentiation. In mice with mTORC1 loss of function, we found that Rho kinase (ROCK) signaling was constitutively activated, resulting in increased cytoskeletal tension and impaired cell-cell adhesion. Inhibition or silencing of ROCK1 was sufficient to rescue keratinocyte adhesion and biochemical differentiation in these mice. mTORC1 loss of function also resulted in marked feedback upregulation of upstream TGF-β signaling, triggering ROCK activity and its downstream effects on desmosomal gene expression. These findings elucidate a role for mTORC1 in the regulation of epithelial barrier formation, cytoskeletal tension, and cell adhesion, underscoring the complexity of signaling feedback following mTORC1 inhibition.

中文翻译：

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mTORC1丢失通过TGF-β/ Rho激酶激活削弱表皮粘附

尽管其在致癌细胞内信号传导网络中的中心地位，但尚未在体内广泛研究mTORC1在上皮发育中的作用。在这里，我们已经使用表皮作为模型系统来阐明上皮组织中mTORC1功能丧失的细胞效应和信号反馈后遗症。在有条件的表皮丧失mTORC1成分的Rheb或Rptor小鼠中，mTORC1功能丧失意外导致表皮擦伤，水疱和出生后早期致死的严重皮肤屏障缺陷，这是由于表皮变薄，桥粒蛋白表达降低和生化分化不完全所致。在具有mTORC1功能丧失的小鼠中，我们发现Rho激酶（ROCK）信号被组成性激活，导致细胞骨架张力增加和细胞黏附受损。ROCK1的抑制或沉默足以挽救这些小鼠的角质形成细胞粘附和生化分化。mTORC1功能丧失还导致上游TGF-β信号的明显反馈上调，触发ROCK活性及其对桥粒基因表达的下游影响。这些发现阐明了mTORC1在调节上皮屏障形成中的作用，