Sardi S Pablo, Murtie Joshua, Koirala Samir, Patten Brooke A, Corfas Gabriel
Neurobiology Program and Department of Neurology, Children's Hospital and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA.
Cell. 2006 Oct 6;127(1):185-97. doi: 10.1016/j.cell.2006.07.037.
Embryonic multipotent neural precursors are exposed to extracellular signals instructing them to adopt different fates, neuronal or glial. However, the mechanisms by which precursors integrate these signals to make timely fate choices remained undefined. Here we show that direct nuclear signaling by a receptor tyrosine kinase inhibits the responses of precursors to astrocyte differentiation factors while maintaining their neurogenic potential. Upon neuregulin-induced activation and presenilin-dependent cleavage of ErbB4, the receptor's intracellular domain forms a complex with TAB2 and the corepressor N-CoR. This complex undergoes nuclear translocation and binds promoters of astrocytic genes, repressing their expression. Consistent with this observation, astrogenesis occurs precociously in ErbB4 knockout mice. Our studies define how presenilin-dependent nuclear signaling by a receptor tyrosine kinase directly regulates gene transcription and cell fate. This pathway could be of importance for neural stem cell biology and for understanding the pathogenesis of Alzheimer's disease.
胚胎多能神经前体细胞会接触到细胞外信号，这些信号指导它们选择不同的命运，即神经元或神经胶质细胞命运。然而，前体细胞整合这些信号以做出适时命运选择的机制仍不清楚。在此我们表明，受体酪氨酸激酶介导的直接核信号传导抑制了前体细胞对星形胶质细胞分化因子的反应，同时维持了它们的神经发生潜能。在神经调节蛋白诱导的ErbB4激活和早老素依赖性切割后，该受体的细胞内结构域与TAB2和共抑制因子N-CoR形成复合物。该复合物发生核转位并结合星形胶质细胞基因的启动子，抑制它们的表达。与这一观察结果一致，在ErbB4基因敲除小鼠中星形胶质细胞生成过早发生。我们的研究确定了受体酪氨酸激酶介导的早老素依赖性核信号传导如何直接调节基因转录和细胞命运。该途径可能对神经干细胞生物学以及理解阿尔茨海默病的发病机制具有重要意义。
