ena-STUDY-FUNCTIONAL GENOMICS CENTER ZURICH-23-06-2017-08:14:34:116-275
Ttc7 in lymphocytes and fibroblasts is a critical regulator of epithelial proliferation in the mouse
Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue Ttc7 result in a multisystemic disease, mostly affecting epithelial barriers and immune defence. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening. Consequently, there is an ongoing debate of whether TTC7A mutations dysregulate epithelial cells only, or whether a cell-intrinsic defect in lymphocytes contributes to disease manifestations. Here, we have shown that severity of epithelial hyperproliferation was accentuated by lymphocytes in a Ttc7-mutated mouse model, whereas the phenotype was not induced by the transfer of Ttc7-mutated hematopoietic cells. Mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. In a xenograft model, Ttc7-mutated mouse fibroblasts induced markedly increased epithelial proliferation of human keratinocytes. Thus, Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. Our results reveal a previously unsuspected, fundamental role of Ttc7 in the communication between cells and stress the need of molecular targeted treatment strategies to tune collective cell behaviour.
Mutations in tetratricopeptide repeat domain 7A (TTC7A) and its mouse orthologue Ttc7 result in a multisystemic disease, mostly affecting epithelial barriers and immune defence. Despite successful hematopoietic stem cell transplantation, ongoing progression of gastrointestinal manifestations can be life-threatening. Consequently, there is an ongoing debate of whether TTC7A mutations dysregulate epithelial cells only, or whether a cell-intrinsic defect in lymphocytes contributes to disease manifestations. Here, we have shown that severity of epithelial hyperproliferation was accentuated by lymphocytes in a Ttc7-mutated mouse model, whereas the phenotype was not induced by the transfer of Ttc7-mutated hematopoietic cells. Mice completely lacking the lymphocytic compartment were not protected from epithelial hyperproliferation. In a xenograft model, Ttc7-mutated mouse fibroblasts induced markedly increased epithelial proliferation of human keratinocytes. Thus, Ttc7-mutated fibroblasts were identified as potent instigators of epithelial hyperproliferation. Our results reveal a previously unsuspected, fundamental role of Ttc7 in the communication between cells and stress the need of molecular targeted treatment strategies to tune collective cell behaviour.