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Foxa2-dependent uterine glandular cell differentiation is essential for successful implantation

Author

Listed:
  • Zhaoyu Jia

    (Shandong University)

  • Bo Li

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

  • Mitsunori Matsuo

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati
    University of Tokyo)

  • Amanda Dewar

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

  • Anxhela Mustafaraj

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

  • Sudhansu K. Dey

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

  • Jia Yuan

    (Shandong University)

  • Xiaofei Sun

    (Cincinnati Children’s Hospital Medical Center
    University of Cincinnati)

Abstract

Uterine receptivity is essential for successful implantation. In mice, uterine receptivity begins with the secretion of LIF from uterine glands stimulated by estrogen on the morning of day 4 pregnancy. We hypothesize that gland readiness for estrogen stimulation is indispensable for uterine receptivity. The current study reveals that uterine glands undergo a differentiation process with expanded branching during the preimplantation period. The single-cell RNA profiling of glandular cells identifies that LIF is expressed exclusively in a Prss29+ subgroup of glandular cells on day 4 of pregnancy. Interestingly, Foxa2-deficient glands lacking LIF production fail to develop branches and the functional Prss29+ subgroup. This Prss29+ subgroup develops prior to estrogen secretion. Collectively, our findings show that uterine glands undergo a FOXA2-dependent maturation process to acquire the competence, named “transitional phase”, for entering the receptive phase. The “transitional phase”, predicting uterine receptivity one day before implantation, is a landmark concept in uterine receptivity.

Suggested Citation

  • Zhaoyu Jia & Bo Li & Mitsunori Matsuo & Amanda Dewar & Anxhela Mustafaraj & Sudhansu K. Dey & Jia Yuan & Xiaofei Sun, 2025. "Foxa2-dependent uterine glandular cell differentiation is essential for successful implantation," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57848-w
    DOI: 10.1038/s41467-025-57848-w
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    References listed on IDEAS

    as
    1. Ralph Stadhouders & Guillaume J. Filion & Thomas Graf, 2019. "Transcription factors and 3D genome conformation in cell-fate decisions," Nature, Nature, vol. 569(7756), pages 345-354, May.
    2. Rong Li & Tianyuan Wang & Ryan M. Marquardt & John P. Lydon & San-Pin Wu & Francesco J. DeMayo, 2023. "TRIM28 modulates nuclear receptor signaling to regulate uterine function," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    3. Jia Yuan & Wenbo Deng & Jeeyeon Cha & Xiaofei Sun & Jean-Paul Borg & Sudhansu. K. Dey, 2018. "Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
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