Division of Molecular Neurobiology, Department of Medical Biochemistry and Biophysics, Karolinska Institute, 171 77 Stockholm, Sweden.
Proc Natl Acad Sci U S A. 2011 Apr 5;108(14):5837-42. doi: 10.1073/pnas.1014993108. Epub 2011 Mar 21.
Adult neural stem cell proliferation is dynamic and has the potential for massive self-renewal yet undergoes limited cell division in vivo. Here, we report an epigenetic mechanism regulating proliferation and self-renewal. The recruitment of the PI3K-related kinase signaling pathway and histone H2AX phosphorylation following GABA(A) receptor activation limits subventricular zone proliferation. As a result, NSC self-renewal and niche size is dynamic and can be directly modulated in both directions pharmacologically or by genetically targeting H2AX activation. Surprisingly, changes in proliferation have long-lasting consequences on stem cell numbers, niche size, and neuronal output. These results establish a mechanism that continuously limits proliferation and demonstrates its impact on adult neurogenesis. Such homeostatic suppression of NSC proliferation may contribute to the limited self-repair capacity of the damaged brain.
成体神经干细胞的增殖是动态的，具有大规模自我更新的潜力，但在体内的细胞分裂受到限制。在这里，我们报告了一种调节增殖和自我更新的表观遗传机制。GABA(A)受体激活后，PI3K 相关激酶信号通路的募集和组蛋白 H2AX 的磷酸化限制了侧脑室下区的增殖。结果，NSC 的自我更新和小生境的大小是动态的，可以通过药理学或通过遗传靶向 H2AX 激活在两个方向上直接调节。令人惊讶的是，增殖的变化对干细胞数量、小生境大小和神经元输出有持久的影响。这些结果建立了一种连续限制增殖的机制，并证明了其对成体神经发生的影响。这种对 NSC 增殖的同源抑制可能有助于受损大脑的自我修复能力有限。
