Coro2a, An Expression Quantitative Trait Gene Underlying Estq1, Controls Uterine Responsiveness to Estradiol

Abstract

The response of the uterus to 17β-estradiol (E2) is genetically controlled, with marked variation observed depending on the mouse strain studied. Previous studies from our laboratory using high (C57BL6/J; B6) and low uterine responders (C3H/HeJ; C3H) to E2 led to the identification of Estq1-Estq5, five quantitative trait loci (QTL) controlling phenotypic variation in uterine growth and eosinophilic leukocyte infiltration. Transcriptional profiling subsequently identified coronin actin binding protein 2A (Coro2a) as a candidate for an expression quantitative trait gene (eQTG) underlying Estq1. Here we show that like mRNA expression, allele specific expression of CORO2A in both the uterine epithelium and stroma similarly co-segregates with uterine responsiveness. Utilizing B6.C3H congenic mice carrying the Coro2aC3H allele, we confirm the genetic linkage between Coro2a and Estq1. Lastly, we show that B6-Coro2a-/- and B6-Coro2aB6/- mice phenocopy uterine responsiveness of mice carrying the Coro2aC3H/C3H and Coro2aB6/C3H alleles respectively, consistent with a haploinsufficiency model of genetic control. Together, these results identify Coro2a as the eQTG underlying Estq1, and establish a critical role for Coro2a in E2-regulated responses.