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Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent,  Lgr5 -expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ  Lgr5-2A-EGFP/CreERT2/DTR  mouse models to identify  Lgr5 -expressing cells in the developing uterus and to evaluate their stem cell identity and function.  Lgr5  is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5 high  cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5 neg  epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5 high  stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5 +  stem/progenitor cells to uterine disorders.

Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development