Title | Loss of NARS1 impairs progenitor proliferation in cortical brain organoids and leads to microcephaly. |
Publication Type | Journal Article |
Year of Publication | 2020 |
Authors | Wang, L, Li, Z, Sievert, D, Smith, DEC, Mendes, MI, Chen, DY, Stanley, V, Ghosh, S, Wang, Y, Kara, M, Aslanger, ADilruba, Rosti, RO, Houlden, H, Salomons, GS, Gleeson, JG |
Journal | Nat Commun |
Volume | 11 |
Issue | 1 |
Pagination | 4038 |
Date Published | 2020 08 12 |
ISSN | 2041-1723 |
Keywords | Adolescent, Adult, Aspartate-tRNA Ligase, Base Sequence, Cell Differentiation, Cell Proliferation, Cell Size, Cell Survival, Cerebral Cortex, Child, Family, Female, Fibroblasts, HEK293 Cells, Humans, Induced Pluripotent Stem Cells, Ki-67 Antigen, Male, Microcephaly, Mutation, Neural Stem Cells, Neuroglia, Organoids, Pedigree, RNA, Transfer, Amino Acyl, Young Adult |
Abstract | Asparaginyl-tRNA synthetase1 (NARS1) is a member of the ubiquitously expressed cytoplasmic Class IIa family of tRNA synthetases required for protein translation. Here, we identify biallelic missense and frameshift mutations in NARS1 in seven patients from three unrelated families with microcephaly and neurodevelopmental delay. Patient cells show reduced NARS1 protein, impaired NARS1 activity and impaired global protein synthesis. Cortical brain organoid modeling shows reduced proliferation of radial glial cells (RGCs), leading to smaller organoids characteristic of microcephaly. Single-cell analysis reveals altered constituents of both astrocytic and RGC lineages, suggesting a requirement for NARS1 in RGC proliferation. Our findings demonstrate that NARS1 is required to meet protein synthetic needs and to support RGC proliferation in human brain development. |
DOI | 10.1038/s41467-020-17454-4 |
Alternate Journal | Nat Commun |
PubMed ID | 32788587 |
PubMed Central ID | PMC7424529 |
Grant List | UM1 HG008900 / HG / NHGRI NIH HHS / United States U54 HG003067 / HG / NHGRI NIH HHS / United States / HH / Howard Hughes Medical Institute / United States R01 NS048453 / NS / NINDS NIH HHS / United States U54 HG006504 / HG / NHGRI NIH HHS / United States R01 NS052455 / NS / NINDS NIH HHS / United States T32 GM008666 / GM / NIGMS NIH HHS / United States |