A "Four Core Genotypes" rat model to distinguish mechanisms underlying sex-biased phenotypes and diseases. bioRxiv 2023 Feb 10
Date
02/18/2023Pubmed ID
36798326Pubmed Central ID
PMC9934672DOI
10.1101/2023.02.09.527738Abstract
BACKGROUND: We have generated a rat model similar to the Four Core Genotypes mouse model, allowing comparison of XX and XY rats with the same type of gonad. The model detects novel sex chromosome effects (XX vs. XY) that contribute to sex differences in any rat phenotype.
METHODS: XY rats were produced with an autosomal transgene of Sry , the testis-determining factor gene, which were fathers of 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 that have XX and XY progeny with ovaries. 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).
RESULTS: We have measured numerous phenotypes to characterize this model, 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. Numerous phenotypes previously found 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 a powerful new model to discriminate sex chromosome and gonadal hormone effects that cause sexual differences in rat physiology and disease.
Author List
Arnold AP, Chen X, Grzybowski MN, Ryan JM, Sengelaub DR, Mohanroy T, Furlan VA, Grisham W, Malloy L, Takizawa A, Wiese CB, Vergnes L, Skaletsky H, Page DC, Reue K, Harley VR, Dwinell MR, Geurts AMAuthors
Melinda R. Dwinell PhD Professor in the Physiology department at Medical College of WisconsinAron Geurts PhD Professor in the Physiology department at Medical College of Wisconsin
