RBPjκ-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development
RBPjκ-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development
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DOI：
10.1242/dev.042911
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发表时间：
2010-05-01
期刊：
影响因子：
4.6
通讯作者：
Hilton, Matthew J.
中科院分区：
文献类型：
--
作者：
Dong, Yufeng;Jesse, Alana M.;Hilton, Matthew J.
Notch通路最近被认为与间充质祖细胞(MPC)从骨髓来源的祖细胞分化有关。然而，Notch是否以RBPj kappa依赖的方式调节MPC的分化，指定特定的MPC细胞命运，调控MPC在骨骼发育早期的增殖和分化，还是控制特定的Notch靶基因来调控这些过程，目前尚不清楚。为了确定Notch通路在MPC骨骼发育过程中的确切作用和作用模式，我们分析了组织特异性功能丧失(Prx1Cre；Rbpjk(f/f))、功能获得(Prx1Cre；ROSA-NICDf/+)和RBPj kappa非依赖性Notch功能获得(Prx1Cre；Rosa-NICDf/+；Rbpjk(f/f))小鼠在MPC增殖和分化中的缺陷。这些数据首次证明，依赖于RBPj kappa的Notch信号通路是骨骼发育过程中MPC增殖和分化的重要调节因子。我们的研究还表明，Notch通路是一种不偏向谱系分配的MPC分化的一般抑制因子。最后，Hes1被鉴定为一个依赖RBPj kappa的Notch靶基因，对MPC的维持和体外软骨形成的抑制非常重要。
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 RBPj kappa-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-NICDf/+) and RBPj kappa-independent Notch gain-of-function (Prx1Cre; Rosa-NICDf/+; Rbpjk(f/f)) mice for defects in MPC proliferation and differentiation. These data demonstrate for the first time that the RBPj kappa-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 RBPj kappa-dependent Notch target gene important for MPC maintenance and the suppression of in vitro chondrogenesis.