Heterogeneous nuclear ribonucleoprotein U (HNRNPU) safeguards the developing mouse cortex

Tamar Sapir, Aditya Kshirsagar, Anna Gorelik, Tsviya Olender, Ziv Porat, Ingrid E. Scheffer, David B. Goldstein, Orrin Devinsky and Orly Reiner ()
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Tamar Sapir: Weizmann Institute of Science
Aditya Kshirsagar: Weizmann Institute of Science
Anna Gorelik: Weizmann Institute of Science
Tsviya Olender: Weizmann Institute of Science
Ziv Porat: Weizmann Institute of Science
Ingrid E. Scheffer: Austin Health and Royal Children’s Hospital, Florey and Murdoch Children’s Research Institutes
David B. Goldstein: Columbia University
Orrin Devinsky: NYU Langone Medical Center, NYU
Orly Reiner: Weizmann Institute of Science

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract HNRNPU encodes the heterogeneous nuclear ribonucleoprotein U, which participates in RNA splicing and chromatin organization. Microdeletions in the 1q44 locus encompassing HNRNPU and other genes and point mutations in HNRNPU cause brain disorders, including early-onset seizures and severe intellectual disability. We aimed to understand HNRNPU’s roles in the developing brain. Our work revealed that HNRNPU loss of function leads to rapid cell death of both postmitotic neurons and neural progenitors, with an apparent higher sensitivity of the latter. Further, expression and alternative splicing of multiple genes involved in cell survival, cell motility, and synapse formation are affected following Hnrnpu’s conditional truncation. Finally, we identified pharmaceutical and genetic agents that can partially reverse the loss of cortical structures in Hnrnpu mutated embryonic brains, ameliorate radial neuronal migration defects and rescue cultured neural progenitors’ cell death.

Date: 2022
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DOI: 10.1038/s41467-022-31752-z

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