Yang Mei, Yang Si-Lu, Herrlinger Stephanie, Liang Chen, Dzieciatkowska Monika, Hansen Kirk C, Desai Ridham, Nagy Andras, Niswander Lee, Moss Eric G, Chen Jian-Fu
Department of Genetics, Biochemistry & Molecular Biology, University of Georgia, Athens, GA 30602, USA.
Department of Biochemistry & Molecular Genetics, University of Colorado Denver, Aurora, CO 80045, USA.
Development. 2015 May 1;142(9):1616-27. doi: 10.1242/dev.120543.
Neural progenitor cells (NPCs) have distinct proliferation capacities at different stages of brain development. Lin28 is an RNA-binding protein with two homologs in mice: Lin28a and Lin28b. Here we show that Lin28a/b are enriched in early NPCs and their expression declines during neural differentiation. Lin28a single-knockout mice show reduced NPC proliferation, enhanced cell cycle exit and a smaller brain, whereas mice lacking both Lin28a alleles and one Lin28b allele display similar but more severe phenotypes. Ectopic expression of Lin28a in mice results in increased NPC proliferation, NPC numbers and brain size. Mechanistically, Lin28a physically and functionally interacts with Imp1 (Igf2bp1) and regulates Igf2-mTOR signaling. The function of Lin28a/b in NPCs could be attributed, at least in part, to the regulation of their mRNA targets that encode Igf1r and Hmga2. Thus, Lin28a and Lin28b have overlapping functions in temporally regulating NPC proliferation during early brain development.
神经祖细胞（NPCs）在大脑发育的不同阶段具有不同的增殖能力。Lin28是一种RNA结合蛋白，在小鼠中有两个同源物：Lin28a和Lin28b。在这里，我们表明Lin28a/b在早期NPCs中富集，并且它们的表达在神经分化过程中下降。Lin28a单敲除小鼠显示NPC增殖减少、细胞周期退出增强和脑体积减小，而同时缺失两个Lin28a等位基因和一个Lin28b等位基因的小鼠表现出相似但更严重的表型。在小鼠中异位表达Lin28a会导致NPC增殖增加、NPC数量增加和脑体积增大。从机制上讲，Lin28a与Imp1（Igf2bp1）在物理和功能上相互作用，并调节Igf2-mTOR信号通路。Lin28a/b在NPCs中的功能至少部分可归因于对编码Igf1r和Hmga2的mRNA靶标的调节。因此，Lin28a和Lin28b在早期大脑发育过程中对NPC增殖的时间调节方面具有重叠功能。
