Lin28-mediated temporal promotion of protein synthesis is crucial for neural progenitor cell maintenance and brain development in mice.
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 (Rpl24 ) as a genetic tool to dampen global protein synthesis, we found that Lin28a compound mutants exhibited NTDs resembling those seen in Lin28a/b dKO mice. Increased NPC numbers and brain sizes in Lin28a-overexpressing mice were rescued by Rpl24 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.
['Herrlinger|Stephanie|S|', 'Shao|Qiang|Q|0000-0001-5307-8264', 'Yang|Mei|M|', 'Chang|Qing|Q|', 'Liu|Yang|Y|', 'Pan|Xiaohan|X|', 'Yin|Hang|H|', 'Xie|Li-Wei|LW|', 'Chen|Jian-Fu|JF|0000-0002-8869-5913']
D000818:Animals D001921:Brain D002453:Cell Cycle D005260:Female D006579:Heterozygote D008297:Male D051379:Mice D018345:Mice, Knockout D058953:Neural Stem Cells D009436:Neural Tube Defects D016601:RNA-Binding Proteins D012270:Ribosomes
Protein synthesis Neural progenitor cell Lin28 Neural tube defect Ribosome biogenesis