Han Dasol, Byun Sung-Hyun, Park Soojeong, Kim Juwan, Kim Inhee, Ha Soobong, Kwon Mookwang, Yoon Keejung
College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, South Korea.
College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon, Gyeonggi-do 440-746, South Korea.
Biochem Biophys Res Commun. 2015 Feb 27;458(1):110-6. doi: 10.1016/j.bbrc.2015.01.077. Epub 2015 Jan 26.
Mammalian brain development is regulated by multiple signaling pathways controlling cell proliferation, migration and differentiation. Here we show that YAP/TAZ enhance embryonic neural stem cell characteristics in a cell autonomous fashion using diverse experimental approaches. Introduction of retroviral vectors expressing YAP or TAZ into the mouse embryonic brain induced cell localization in the ventricular zone (VZ), which is the embryonic neural stem cell niche. This change in cell distribution in the cortical layer is due to the increased stemness of infected cells; YAP-expressing cells were colabeled with Sox2, a neural stem cell marker, and YAP/TAZ increased the frequency and size of neurospheres, indicating enhanced self-renewal- and proliferative ability of neural stem cells. These effects appear to be TEA domain family transcription factor (Tead)-dependent; a Tead binding-defective YAP mutant lost the ability to promote neural stem cell characteristics. Consistently, in utero gene transfer of a constitutively active form of Tead2 (Tead2-VP16) recapitulated all the features of YAP/TAZ overexpression, and dominant negative Tead2-EnR resulted in marked cell exit from the VZ toward outer cortical layers. Taken together, these results indicate that the Tead-dependent YAP/TAZ signaling pathway plays important roles in neural stem cell maintenance by enhancing stemness of neural stem cells during mammalian brain development.
哺乳动物的大脑发育受多种控制细胞增殖、迁移和分化的信号通路调节。在此，我们使用多种实验方法表明，YAP/TAZ以细胞自主方式增强胚胎神经干细胞特征。将表达YAP或TAZ的逆转录病毒载体导入小鼠胚胎大脑，可诱导细胞定位于脑室区（VZ），即胚胎神经干细胞龛。皮质层中细胞分布的这种变化是由于受感染细胞干性增加所致；表达YAP的细胞与神经干细胞标志物Sox2共标记，且YAP/TAZ增加了神经球的频率和大小，表明神经干细胞的自我更新和增殖能力增强。这些效应似乎依赖于TEA结构域家族转录因子（Tead）；一种Tead结合缺陷型YAP突变体失去了促进神经干细胞特征的能力。同样，在子宫内基因转移组成型激活形式的Tead2（Tead2-VP16）概括了YAP/TAZ过表达的所有特征，而显性负性Tead2-EnR导致细胞从VZ显著向外皮质层迁移。综上所述，这些结果表明，依赖Tead的YAP/TAZ信号通路在哺乳动物大脑发育过程中通过增强神经干细胞的干性，在神经干细胞维持中发挥重要作用。
