A humanized NOVA1 splicing factor alters mouse vocal communications
NOVA1, a neuronal RNA-binding protein expressed in the central nervous system, is essential for survival in mice and normal development in humans. A single amino acid change (I197V) in NOVA1's second RNA binding domain is unique to modern humans. To study its physiological effects, we generated mice carrying the human-specific I197V variant (Nova1<sup>hu/hu</sup>) and analyzed the molecular and behavioral consequences. While the I197V substitution had minimal impact on NOVA1's RNA binding capacity, it led to specific effects on alternative splicing, and CLIP revealed multiple binding peaks in mouse brain transcripts involved in vocalization. These molecular findings were associated with behavioral differences in vocalization patterns in Nova1<sup>hu/hu</sup> mice as pups and adults. Our findings suggest that this human-specific NOVA1 substitution may have been part of an ancient evolutionary selective sweep in a common ancestral population of Homo sapiens, possibly contributing to the development of spoken language through differential RNA regulation during brain development.
Authors
- Ji‐Dung Luo (ORCID: https://orcid.org/0000-0003-0150-1440)
- Laís Ceschini Machado (ORCID: https://orcid.org/0000-0003-2747-8613)
- Erich D. Jarvis (ORCID: https://orcid.org/0000-0001-8931-5049)
- Yoko Tajima (ORCID: https://orcid.org/0000-0002-0914-6394)
- Nurdan Kuru (ORCID: https://orcid.org/0000-0001-8184-7809)
- Robert B. Darnell (ORCID: https://orcid.org/0000-0002-5134-8088)
- César D. M. Vargas (ORCID: https://orcid.org/0000-0002-8493-2504)
- Keiichi Ito (ORCID: https://orcid.org/0000-0002-9704-5058)
- Jiawei Xing (ORCID: https://orcid.org/0000-0002-7691-1180)
- Adam Siepel (ORCID: https://orcid.org/0000-0002-3557-7219)
- Wei Wang (ORCID: https://orcid.org/0000-0002-3216-7118)
- Thomas S. Carroll
Institutions
- Howard Hughes Medical Institute (US)
- Cold Spring Harbor Laboratory (US)
- Rockefeller University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-02-18
- DOI
- https://doi.org/10.1038/s41467-025-56579-2
- Citations
- 13
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 10.48
Funders
- W. M. Keck Foundation
- National Institutes of Health
- Simons Center for Quantitative Biology, Cold Spring Harbor Laboratory
- Japan Society for the Promotion of Science
- National Institute of Neurological Disorders and Stroke