{"doi":"10.1093/biolre/ioad152","title":"Uterine glands originate from islands of FOXA2-positive luminal epithelium cells that differentiate de novo and invade uterine stroma","abstract":"Dear editor, The onset of bovine uterine gland development (adenogenesis) can occur in utero (late gestation) or shortly after birth making cattle distinctly different from most other farm and laboratory species where gland development is postnatal [1–3]. Regardless of the timing, the development of uterine glands in all mammalian uteri is initiated with the differentiation of luminal epithelium (LE) into glandular epithelium (GE). The cells of the LE rupture the basement membrane and penetrate the underlying stroma forming a bud and subsequent tube-like structures lined with GE. Later, these GE-lined tubes elongate, coil and branch to form the mature glands of the endometrium [4, 5]. A universal feature of the GE is the expression of Forkhead box A2 (FOXA2); a transcription factor from the fork-head transcription factor subfamily [6]. Importantly, FOXA2 is expressed specifically in the developing and the adult GE but is absent in the LE. Global knock-out of Foxa2 is embryonic lethal in mice [7]. Subsequent studies of conditional deletion of Foxa2 in the neonatal mouse uterus (using Pgr-Cre) inhibited formation of glands and led to infertility secondary to an aglandular endometrium [3]. Conditional deletion of Foxa2 in the adult uterus (using Ltf-Cre) led to a morphologically normal uterus that failed to maintain pregnancy [3]. Failure to maintain pregnancy was explained by the loss of LIF expression, an essential embryokine, within the Foxa2 knockout glands [8]. These studies demonstrated the central role that FOXA2 plays in the formation and function of uterine glands. Uterine glands knocked out in neonatal ovine uteri (UGKO model) led to infertility and confirmed that uterine glands are essential for fertility in ruminants as well [9]. Immunohistochemistry for FOXA2 transcription factor and MKI67 cellular proliferation marker in neonatal calves at PND0, 7, 14, and 28. (A) PND0 calf without glandular development showing dispersed FOXA2+ and MKI67+ cells within the LE of ICAR endometrium at two locations (Boxes 1 and 2). (B) PND0 calf with regions of aglandular CAR and glandular ICAR endometrium immunostained for FOXA2 and MKI67. Within the ICAR endometrium there are islands of FOXA2+ cells that are confined to the LE (Box 1; middle top panel) and also dispersed MKI67+ cells (middle bottom panel). There are also regions with developing tubular glands (Box 2) that are FOXA2+ (right top panel) and MKI67+ at the gland tips (right bottom panel). (C) Uterine glandular development on PND 7 (left), 14 (middle), and 28 (right) showing islands of FOXA2+ cells in the LE (top panels) that are not associated with MKI67+ cells (bottom panels). (D) Serial sections through islands of FOXA2+ cells (Box 1 middle and Box 2 right) demonstrating FOXA2+ cells across seven serial sections (middle) and contiguous staining of FOXA2+ islands with gland buds. Our lab studies the interaction between the microbiome and tissue regeneration in the postpartum bovine uterus (uterine involution). Part of this process involves the restoration of uterine glands that may arise from existing glands [10] or perhaps arise from the development of new glands de novo. We elected to use neonatal calves as a model to study the earliest phases of glandular development in the bovine. We found that the LE invaginates into the stroma to form a bud and subsequently tubules before coiling and branching (as expected). To our surprise, however, expression of FOXA2 protein occurred in patches of cells (islands) within the LE before glands formed. The first phase of glandular development in the bovine, therefore, was the formation of islands of FOXA2-positive (+) cells within the LE that then appeared to direct the formation of glands into the underlying stroma. This is distinctly different from the current conceptual model that FOXA2+ cells are found within the GE after the gland has formed, but not prior to [2, 3]. We performed immunohistochemistry on 5 μm cross sections to ev","journal":"Biology of Reproduction","year":2023,"id":379998,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9483,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1076922,"name":"M.O. Caldeira","orcid":"0000-0002-1272-1249","position":1,"is_corresponding":false},{"id":1145121,"name":"Amanda L. Patterson","orcid":"0000-0001-8407-5437","position":2,"is_corresponding":false},{"id":373803,"name":"M.C. Lucy","orcid":"0000-0001-5771-9460","position":3,"is_corresponding":false},{"id":1076921,"name":"Isabella Sellmer Ramos","orcid":"0000-0003-3556-5709","position":0,"is_corresponding":true}],"reference_count":11,"raw_metadata":null,"created_at":"2026-07-19T01:17:00.789848Z","pmid":"37962938","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}