New allele of mouse DNA/RNA helicase senataxin causes meiotic arrest and infertility
Document Type
Article
Publication Date
11-2023
Original Citation
Fujiwara Y,
Saito K,
Sun F,
Petri S,
Inoue E,
Schimenti J,
Okada Y,
Handel M.
New allele of mouse DNA/RNA helicase senataxin causes meiotic arrest and infertility Reproduction. 2023;166(6):437-50.
Keywords
JMG, SS1
JAX Source
Reproduction. 2023;166(6):437-50.
PMID
37801077
DOI
https://doi.org/10.1530/REP-23-0166
Grant
This work was supported by the NIH grant, HD42137 to the Reproductive Genomics Program at The Jackson Laboratory, Japan Society for the Promotion of Science (JSPS), Strategic Young Researcher Oversea Visits Program for Acceleration Brain Circulation (to YF), and JSPS KAKENHI grant number 21K15005 (to YF), the program of the Joint Usage/IMEG Research Center for Developmental Medicine, Kumamoto University (to YF). Grant Program for Research Study from the Nakatani Foundation (to YF).
Abstract
An unbiased screen for discovering novel mouse genes for fertility identified the spcar3, spermatocyte arrest 3, mutant phenotype. The spcar3 mutation identified a new allele of the Setx gene, encoding senataxin, a DNA/RNA helicase that regulates transcription termination by resolving DNA/RNA hybrid R-loop structures. The Setxspcar3 mutant mice exhibit male infertility and female subfertility. Histology of the Setxspcar3 mutant testes revealed the absence of spermatids and mature spermatozoa in the seminiferous tubules. Cytological analysis of chromosome preparations of the Setxspcar3 mutant spermatocytes revealed normal synapsis, but aberrant DNA damage in the autosomes, defective formation of the sex body, and arrest of meiosis in mid-prophase. Additionally, Setxspcar3 testicular cells exhibit abnormal accumulation of R-loops. Transient expression assays identified regions of the senataxin protein required for sub-nuclear localization. Together, these results not only confirm that senataxin is required for normal meiosis and spermatogenesis but also provide a new resource for the determination of its role in maintaining R-loop formation and genome integrity.