Department of Orthopaedics and Rehabilitation, Center for Musculoskeletal Research, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Development. 2010 May;137(9):1461-71. doi: 10.1242/dev.042911. Epub 2010 Mar 24.
The Notch pathway has recently been implicated in mesenchymal progenitor cell (MPC) differentiation from bone marrow-derived progenitors. However, whether Notch regulates MPC differentiation in an RBPjkappa-dependent manner, specifies a particular MPC cell fate, regulates MPC proliferation and differentiation during early skeletal development or controls specific Notch target genes to regulate these processes remains unclear. To determine the exact role and mode of action for the Notch pathway in MPCs during skeletal development, we analyzed tissue-specific loss-of-function (Prx1Cre; Rbpjk(f/f)), gain-of-function (Prx1Cre; Rosa-NICD(f/+)) and RBPjkappa-independent Notch gain-of-function (Prx1Cre; Rosa-NICD(f/+); Rbpjk(f/f)) mice for defects in MPC proliferation and differentiation. These data demonstrate for the first time that the RBPjkappa-dependent Notch signaling pathway is a crucial regulator of MPC proliferation and differentiation during skeletal development. Our study also implicates the Notch pathway as a general suppressor of MPC differentiation that does not bias lineage allocation. Finally, Hes1 was identified as an RBPjkappa-dependent Notch target gene important for MPC maintenance and the suppression of in vitro chondrogenesis.
Notch 通路最近被牵涉到骨髓来源祖细胞（MPC）向间质祖细胞分化的过程中。然而，Notch 是否通过 RBPjkappa 依赖性方式调节 MPC 分化，特异性指定特定的 MPC 细胞命运，调节早期骨骼发育过程中的 MPC 增殖和分化，或者控制特定的 Notch 靶基因来调节这些过程，目前仍不清楚。为了确定 Notch 通路在骨骼发育过程中对 MPC 的确切作用和作用方式，我们分析了组织特异性敲除功能（Prx1Cre; Rbpjk(f/f)）、获得功能（Prx1Cre; Rosa-NICD(f/+))和 RBPjkappa 非依赖性 Notch 获得功能（Prx1Cre; Rosa-NICD(f/+); Rbpjk(f/f)）小鼠在 MPC 增殖和分化方面的缺陷。这些数据首次表明，RBPjkappa 依赖性 Notch 信号通路是骨骼发育过程中 MPC 增殖和分化的关键调节因子。我们的研究还表明，Notch 通路是 MPC 分化的一般抑制剂，不偏向谱系分配。最后，鉴定出 Hes1 是 RBPjkappa 依赖性 Notch 靶基因，对于 MPC 的维持和体外软骨形成的抑制非常重要。
