Center for Craniofacial and Molecular Biology, University of Southern California, Los Angeles, CA 90033, USA.
Biomedical and Health Sciences Institute, Department of Genetics, University of Georgia, Athens, GA 30602, USA.
Development. 2019 May 28;146(10):dev173765. doi: 10.1242/dev.173765.
Neural progenitor cells (NPCs) undergo rapid proliferation during neurulation. This rapid growth generates a high demand for mRNA translation in a timing-dependent manner, but its underlying mechanism remains poorly understood. Lin28 is an RNA-binding protein with two paralogs, Lin28a and Lin28b, in mammals. Mice with deletion exhibit no developmental defects, whereas we have previously reported that deletion leads to microcephaly. Here, we find that double knockout (dKO) mice display neural tube defects (NTDs) coupled with reduced proliferation and precocious differentiation of NPCs. Using ribosomal protein 24 hypomorphic mice ( ) as a genetic tool to dampen global protein synthesis, we found that compound mutants exhibited NTDs resembling those seen in dKO mice. Increased NPC numbers and brain sizes in Lin28a-overexpressing mice were rescued by heterozygosity. Mechanistically, polysome profiling revealed reduced translation of genes involved in the regulation of cell cycle, ribosome biogenesis and translation in dKO mutants. Ribosome biogenesis was reduced in dKO and increased in Lin28a-overexpressing NPCs. Therefore, Lin28-mediated promotion of protein synthesis is essential for NPC maintenance and early brain development.
神经祖细胞 (NPC) 在神经胚形成过程中经历快速增殖。这种快速生长以时间依赖的方式产生了对 mRNA 翻译的高需求，但其潜在机制仍知之甚少。Lin28 是一种具有两个同源物 Lin28a 和 Lin28b 的 RNA 结合蛋白。在哺乳动物中，Lin28a 缺失的小鼠没有表现出发育缺陷，而我们之前曾报道过 Lin28b 缺失会导致小头畸形。在这里，我们发现 Lin28b 双敲除 (dKO) 小鼠表现出神经管缺陷 (NTD)，同时 NPC 的增殖减少和早熟分化。使用核糖体蛋白 24 低功能小鼠 ( ) 作为抑制全局蛋白质合成的遗传工具，我们发现 Lin28b 复合突变体表现出类似于 Lin28b dKO 小鼠的 NTD。Lin28a 过表达小鼠中 NPC 数量增加和大脑增大可通过 Lin28b 杂合性得到挽救。从机制上讲，多核糖体分析显示 Lin28b dKO 突变体中参与细胞周期调控、核糖体生物发生和翻译的基因翻译减少。Lin28b dKO 和 Lin28a 过表达 NPC 中的核糖体生物发生减少。因此，Lin28 介导的蛋白质合成促进对于 NPC 维持和早期大脑发育至关重要。
