期刊
DEVELOPMENT
卷 146, 期 10, 页码 -出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/dev.173765
关键词
Lin28; Protein synthesis; Ribosome biogenesis; Neural progenitor cell; Neural tube defect
资金
- Center for Craniofacial Molecular Biology, Herman Ostrow School of Dentistry at the University of Southern California
- National Institutes of Health [R01NS097231, R01NS096176]
- National Institute of Health Blueprint Diversity Specialized Predoctoral to Postdoctoral Advancement in Neuroscience (D-SPAN) award [F99NS105187-01]
- Achievement Rewards for College Scientists (ARCS) Global Impact Award
- National Institutes of Health training grant [2T32GM007103-42]
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 Lin28b deletion exhibit no developmental defects, whereas we have previously reported that Lin28a deletion leads to microcephaly. Here, we find that Lin28a/b double knockout (dKO) mice display neural tube defects (NTDs) coupled with reduced proliferation and precocious differentiation of NPCs. Using ribosomal protein 24 hypomorphic mice (Rp/24(Bstl+)) as a genetic tool to dampen global protein synthesis, we found that Lin28a(-/-);Rp124(Bstl+) compound mutants exhibited NTDs resembling those seen in Lin28alb dKO mice. Increased NPC numbers and brain sizes in Un28a-overexpressing mice were rescued by Rp124(Bstl+) 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.
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