Sry-modified laboratory rat lines to study sex-chromosome effects underlying sex differences in physiology and disease: Four Core Genotypes and more. Biol Sex Differ 2026 Feb 21;17(1)
Date
02/22/2026Pubmed ID
41723549Pubmed Central ID
PMC13067745DOI
10.1186/s13293-026-00837-5Scopus ID
2-s2.0-105035498694 (requires institutional sign-in at Scopus site)Abstract
BACKGROUND: Previous research on Four Core Genotypes and XY* mice has been instrumental in establishing important effects of sex-chromosome complement that cause sex differences in physiology and disease. We have generated rat models using similar modifications of the testis-determining gene Sry, to produce XX and XY rats with the same type of gonad, as well as XO, XXY and XYY rats with varying gonads. The models permit discovery of novel sex-chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype, and test for effects of different numbers of X or Y chromosomes.
METHODS: XY rats were created with an autosomal transgene of Sry, producing XX and XY progeny with testes. In other rats, CRISPR-Cas9 technology was used to remove Y chromosome factors that initiate testis differentiation, producing fertile XY gonadal females. Interbreeding of these lines produced rats with interesting combinations of sex chromosomes and gonads: XO, XX, XY, XXY rats with ovaries; and XO, XX, XY, XXY, and XYY rats with testes. These groups can be compared to detect sex differences caused by sex-chromosome complement (XX vs. XY) and/or by gonadal hormones (rats with testes vs. ovaries). Other comparisons detect the effects of X or Y chromosome number (in gonadal females: XO vs. XX, XX vs. XXY, XO vs. XY, XY vs. XXY; in gonadal males: XY vs. XXY, XY vs. XYY; XX vs. XXY, XO vs. XX, XO vs. XY).
RESULTS: We measured numerous phenotypes to characterize these models, including gonadal histology, breeding performance, anogenital distance, levels of reproductive hormones, body and organ weights, and central nervous system sexual dimorphisms. Serum testosterone levels were comparable in adult XX and XY gonadal males. Phenotypes previously known to be sexually differentiated by the action of gonadal hormones were found to be similar in XX and XY rats with the same type of gonad, suggesting that XX and XY rats with the same type of gonad have comparable levels of gonadal hormones at various stages of development.
CONCLUSION: The results establish powerful new models to discriminate sex-chromosome and gonadal hormone effects that cause sex differences in rat physiology and disease.
Author List
Arnold AP, Chen X, Grzybowski MN, Ryan JM, Sengelaub DR, Mohanroy T, Furlan VA, Schmidtke HR, Prokop JW, Tutaj M, Ciosek JL, Kalbfleisch TS, O'Donnell L, Grisham W, Landen S, Malloy L, Takizawa A, Li K, Barseghyan H, Wiese CB, Vergnes L, Reue K, Wanagat J, Skaletsky H, Page DC, Harley VR, Dwinell MR, Geurts AMAuthors
Melinda R. Dwinell PhD Associate Dean, Professor in the Physiology department at Medical College of WisconsinAron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
Monika Tutaj Research Scientist II in the Physiology department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsFemale
Genes, sry
Genotype
Male
Rats
Rats, Transgenic
Sex Characteristics
Sex-Determining Region Y Protein
Testis
X Chromosome
Y Chromosome
