FOXA2 Biology & Uterine Development

Defects in gland function can result in endometrial pathologies, and uterine luminal fluid may be useful to develop biomarkers for a functionally competent uterus. Given the importance of uterine glands in normal endometrial biology, another research area has focused on determining the biological mechanisms regulating uterine gland morphogenesis using mouse genetic models. Forkhead box proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity in several organs and tissues. In the mouse and human endometrium, Foxa2 is expressed exclusively in glandular epithelial cells and has dual roles in regulation of gland development in the neonate and gland function in the adult. We use Stage- and cell-specific transgenic models of FOXA2 deficiency to study the role of FOXA2 and glands in endometrial biology. For example, ablation of FOXA2 in the neonatal uterus inhibits glandular epithelial differentiation and the uterus of those adult mice (Pgr- Cre FOXA2 cKO) lack glands. In contrast, the uterus of adult mice lacking FOXA2 have glands (Ltf-iCre FOXA2 cKO). Both mouse models are infertile due to recurrent early pregnancy loss because the blastocyst fails to implant. As expected, the glandless uterus of Pgr-Cre FOXA2 cKO mice lacks expression of leukemia inhibitory factor (LIF), which is normally induced in the glandular epithelium by nidatory estrogen and required for uterine receptivity. The uterus of Ltf-iCre cKO mice also lacked LIF expression despite having glands in their endometrium. Although LIF repletion rescued blastocyst implantation in both types of FOXA2 cKO mice, term pregnancy was achieved only in gland containing Ltf-iCre FOXA2 cKO mice. The LIF-replaced glandless Pgr-Cre FOXA2 cKO mice lost their pregnancies after gestational day 6.

An additional line of research in the lab focuses on how FOXA2 mechanistically controls uterine gland function and how its dysregulation contributes to endometrial pathologies. Of note, FOXA2 is a tumor suppressor gene that is down-regulated and silenced or mutated during the development of endometrial cancer.

To this end, we are currently pursuing projects to understand:

  1. The role of glands during the post-implantation period (decidualization and placentation).

  2. How glands and FOXA2 contribute to endometrial regeneration.

  3. The role of the glands and Foxa2 in endometrial pathologies.

All projects use mouse genetic models, endometrial organoid culture (human and mouse), and next-generation sequencing methods.