Loss of PRICKLE1 in the myometrium leads to reduced fertility, abnormal myometrial architecture, and aberrant extracellular matrix deposition in mice.

ABSTRACT: Uterine leiomyomas (UL) are the most prevalent benign tumors of the female reproductive tract, originating from the myometrium and affecting up to 75% of reproductive-age women. Symptoms of UL include pelvic pain, pressure, dysmenorrhea, menorrhagia, anemia, and reproductive dysfunction. Currently, there is no effective long-term pharmacotherapy for UL, making them the leading cause of hysterectomies in the United States. The lack of treatment options is attributed to the absence of accurate animal models and a limited understanding of UL pathogenesis. Previous research has shown the ablation of Rest within the myometrium results in a UL phenotype in mice. PRICKLE1, also known as Rest-interacting LIM-domain Protein (RILP), plays a significant role in the nuclear localization of REST and Wnt/planar cell polarity (PCP) signaling, making it a critical target for UL studies. In the context of PCP, UL structural proteins show abnormal organization, structure, and expression levels, potentially influenced by PRICKLE1 loss. The exact role of PRICKLE1 in UL pathogenesis remains unclear but may be crucial for developing long-term pharmacotherapies. To explore PRICKLE1's role in UL, we developed a myometrial conditional knockout (cKO) of Prickle1 using our myometrial-specific icre. Our findings demonstrate that PRICKLE1 loss in the myometrium results in a UL phenotype characterized by fibrotic structures, excessive extracellular matrix (ECM) production, altered ECM and smooth muscle cell organization, increased Esr1 and Pgr expression, and dysregulated Wnt/PCP signaling. This novel mouse model serves as a valuable preclinical tool for understanding UL pathogenesis and developing future pharmacotherapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE276991 | GEO | 2025/03/13

REPOSITORIES: GEO