Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease.
Overview
- Program in Genetics and Genomics, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA
- Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA
- Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA
- Medical Scientist Training Program, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas 77030, USA
- Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77030, USA
- Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA
Abstract
Many neurological diseases impact specific brain regions despite widespread expression of the disease-related protein. Spinocerebellar ataxia type 1 (SCA1) primarily affects the cerebellum, though Ataxin-1 (ATXN1) is widely expressed. We previously showed that intensified interaction between mutant ATXN1 and Capicua (CIC) drives SCA1 pathogenesis in the cerebellum, whereas ATXN1 loss augments amyloid β production in the hippocampus and cortex. CIC, however, forms a complex with ATXN1 and its paralog, Ataxin-1-like (ATXN1L), yet knockout of either yields completely different phenotypes. To determine whether this could be due to CIC having two isoforms, we generated mice bearing either the long (CIC-L) or short (CIC-S) isoform. Loss of CIC-L led to cognitive deficits, whereas loss of CIC-S caused early postnatal lethality, phenocopying ATXN1 and ATXN1L knockout mice, respectively. Furthermore, CIC-L preferentially interacts with ATXN1, and CIC-S with ATXN1L. Our data underscore the importance of isoform–paralog interplay in studying regional vulnerability in neurodegenerative diseases.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE310453, at NCBI GEO; found in “Data and material availability”
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Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 12 authors, 9 keywords, 9 MeSH terms, 16 funders, 59 references, 1 integrity notice.
Cite
This paper
Lee, H., Gonzalez, E. V., Rivera, E. M., Durham, M. A., Richman, R., Chu, E. H.-Y., Xia, K., Chen, H., Liu, Z., Veeraragavan, S., Shivanna, B., & Zoghbi, H. Y. (2026). Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease. Genes & development, 40(15-16), 1267-1282. https://
BibTeX
@article{lee2026function
author = {Lee, Hamin and Gonzalez, Esmeralda Villavicencio and Rivera, Elias M and Durham, Mark A and Richman, Ronald and Chu, Elizabeth H-Y and Xia, Kailey and Chen, Hu and Liu, Zhandong and Veeraragavan, Surabi and Shivanna, Binoy and Zoghbi, Huda Y},
title = {{Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease}},
journal = {Genes \& development},
year = {2026},
month = aug,
volume = {40},
number = {15-16},
pages = {1267--1282},
publisher = {Cold Spring Harbor Laboratory Press},
issn = {0890-9369},
doi = {10.1101/
url = {https://
pmid = {42476817},
pmcid = {PMC13390769}
}
RIS
TY - JOUR
AU - Lee, Hamin
AU - Gonzalez, Esmeralda Villavicencio
AU - Rivera, Elias M
AU - Durham, Mark A
AU - Richman, Ronald
AU - Chu, Elizabeth H-Y
AU - Xia, Kailey
AU - Chen, Hu
AU - Liu, Zhandong
AU - Veeraragavan, Surabi
AU - Shivanna, Binoy
AU - Zoghbi, Huda Y
TI - Functional divergence of Capicua isoforms explains differential tissue vulnerability in neurological disease
T2 - Genes & development
J2 - Genes Dev
PY - 2026
DA - 2026/
VL - 40
IS - 15-16
SP - 1267
EP - 1282
SN - 0890-9369
PB - Cold Spring Harbor Laboratory Press
DO - 10.1101/
UR - https://
LA - en
ER -
CSL-JSON
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