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Lin28-mediated promotion of protein synthesis is critical for neural progenitor cell maintenance and brain development in mice

ABSTRACT: Neural progenitor cells (NPCs) undergo rapid proliferation during neurulation in early development. This rapid growth generates a high demand for mRNA translation in a timing-dependent manner, but its underlying mechanism and functional importance remain poorly understood. Lin28 is an RNA-binding protein with two paralogs, Lin28a and Lin28b, in mammals. Lin28b deletion exhibited no developmental defects in mice, while we previously reported that Lin28a deletion led to microcephaly. Here we found that Lin28a/b double knockout (dKO) mice displayed neural tube defects (NTDs) coupled with reduced proliferation and precocious differentiation of NPCs. We used ribosomal protein 24 hypomorphic mice (Rpl24Bst/+) as a genetic tool to dampen global protein synthesis. In support of the importance of Lin28-mediated translation promotion, Lin28a-/-;Rpl24Bst/+ compound mutants exhibited NTDs resembling those seen in Lin28a/b dKO mice. Furthermore, increased NPC numbers and brain sizes in Lin28a-overexpressing mice were rescued by Rpl24Bst/+ heterozygosity. Mechanistically, RNA-sequencing of polysome sucrose gradient fractions revealed a reduced translation of genes involved in the regulation of cell cycle, ribosome biogenesis, and translation in mutants. Lin28a localizes in the nucleoli of NPCs, and ribosome biogenesis was reduced in dKO and increased in Lin28a-overexpressing NPCs. Together, these results suggest that Lin28-mediated promotion of protein synthesis is essential for NPC maintenance and early brain development.

ORGANISM(S): Mus musculus

PROVIDER: GSE131536 | GEO | 2019/05/22

REPOSITORIES: GEO

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