Department of Neurology, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Chicago, IL 60611, USA.
Dev Cell. 2013 May 13;25(3):241-55. doi: 10.1016/j.devcel.2013.04.006.
Regulating cell proliferation and differentiation in CNS development requires both extraordinary complexity and precision. Neural progenitors receive graded overlapping signals from midline signaling centers, yet each makes a unique cell fate decision in a spatiotemporally restricted pattern. The Nde1-Lis1 complex regulates individualized cell fate decisions based on the geographical location with respect to the midline. While cells distant from the midline fail to self-renew in the Nde1-Lis1 double-mutant CNS, cells embedded in the signaling centers showed marked overproliferation. A direct interaction between Lis1 and Brap, a mitogen-activated protein kinase (MAPK) signaling threshold modulator, mediates this differential response to mitogenic signal gradients. Nde1-Lis1 deficiency resulted in a spatially dependent alteration of MAPK scaffold Ksr and hyperactivation of MAPK. Epistasis analyses supported synergistic Brap and Lis1 functions. These results suggest that a molecular complex composed of Nde1, Lis1, and Brap regulates the dynamic MAPK signaling threshold in a spatially dependent fashion.
调控中枢神经系统发育中的细胞增殖和分化既需要非凡的复杂性，也需要极高的精确性。神经祖细胞从中线信号中心接收分级重叠的信号，但每个信号中心都以时空受限的模式做出独特的细胞命运决定。Nde1-Lis1 复合物根据与中线的地理位置调节个性化的细胞命运决定。虽然远离中线的细胞在 Nde1-Lis1 双突变中枢神经系统中无法自我更新，但嵌入信号中心的细胞表现出明显的过度增殖。Lis1 与丝裂原活化蛋白激酶 (MAPK) 信号转导阈值调节剂 Brap 之间的直接相互作用介导了对有丝分裂信号梯度的这种差异反应。Nde1-Lis1 缺失导致 MAPK 支架 Ksr 的空间依赖性改变和 MAPK 的过度激活。上位性分析支持 Brap 和 Lis1 功能的协同作用。这些结果表明，由 Nde1、Lis1 和 Brap 组成的分子复合物以空间依赖的方式调节动态 MAPK 信号转导阈值。
