Max Planck Institute of Psychiatry, Molecular Neuroendocrinology, Munich, Germany.
Stem Cells. 2013 Aug;31(8):1621-32. doi: 10.1002/stem.1405.
Cell-fate decisions and differentiation of embryonic and adult neural stem cells (NSC) are tightly controlled by lineage-restricted and temporal factors that interact with cell-intrinsic programs and extracellular signals through multiple regulatory loops. Imprinted genes are important players in neurodevelopment and mental health although their molecular and cellular functions remain poorly understood. Here, we show that the paternally expressed transcriptional regulator Zac1 (zinc finger protein regulating apoptosis and cell cycle arrest) is transiently induced during astroglial and neuronal differentiation of embryonic and adult NSC lines. Thereby, Zac1 transactivates Socs3 (suppressor of cytokine signaling 3), a potent inhibitor of prodifferentiative Jak/Stat3 signaling, in a lineage-specific manner to prevent precocious astroglial differentiation. In vivo, Zac1 and Socs3 colocalize in the neocortical ventricular zone during incipient astrogliogenesis. Zac1 overexpression in primary NSCs delays astroglial differentiation whereas knockdown of Zac1 or Socs3 facilitates formation of astroglial cells. This negative feedback loop is unrelated to Zac1's cell cycle arrest function and specific to the Jak/Stat3 pathway. Hence, reinstating Jak/Stat3 signaling in the presence of increased Zac1 expression allows for timely astroglial differentiation. Overall, we suggest that the imprinted gene Zac1 curtails astroglial differentiation of NSCs in the developing and adult brain.
胚胎和成年神经干细胞（NSC）的细胞命运决定和分化受到谱系限制和时间因素的严格控制，这些因素通过多个调节环与细胞内在程序和细胞外信号相互作用。印迹基因是神经发育和心理健康的重要参与者，尽管它们的分子和细胞功能仍知之甚少。在这里，我们表明，父系表达的转录调节剂 Zac1（锌指蛋白调节细胞凋亡和细胞周期停滞）在胚胎和成年 NSC 系的星形胶质细胞和神经元分化过程中短暂诱导。因此，Zac1 以谱系特异性的方式反式激活 Socs3（细胞因子信号抑制因子 3），这是一种有效的促分化 Jak/Stat3 信号抑制剂，以防止过早的星形胶质细胞分化。在体内，Zac1 和 Socs3 在新皮层脑室区的早期神经胶质发生过程中共同定位。原代 NSCs 中的 Zac1 过表达延迟星形胶质细胞分化，而 Zac1 或 Socs3 的敲低则促进星形胶质细胞的形成。这种负反馈环与 Zac1 的细胞周期阻滞功能无关，而是特定于 Jak/Stat3 通路。因此，在增加 Zac1 表达的情况下恢复 Jak/Stat3 信号可以允许及时的星形胶质细胞分化。总的来说，我们认为印迹基因 Zac1 限制了发育中和成年大脑中 NSCs 的星形胶质细胞分化。
