Transcription Factor 23 is an Essential Determinant of Murine Term Parturition

Abstract

Pregnancy involving intricate tissue transformations governed by the progesterone hormone (P4). P4 signaling via P4 receptors (PRs) is vital for endometrial receptivity, decidualization, myometrial quiescence, and labor initiation. This study explored the role of TCF23 as a downstream target of PR during pregnancy. TCF23 was found to be expressed in female reproductive organs, predominantly in uterine stromal and smooth muscle cells. Tcf23 expression was high during midgestation and was specifically regulated by P4, but not estrogen. The Tcf23 knockout (KO) mouse was generated and analyzed. Female KO mice aged 4-6 months exhibited subfertility, reduced litter size, and defective parturition. Uterine histology revealed disrupted myometrial structure, altered collagen organization, and disarrayed smooth muscle sheets at the conceptus sites of KO mice. RNA-Seq analysis of KO myometrium revealed dysregulation of genes associated with cell adhesion and extracellular matrix organization. TCF23 potentially modulates TCF12 activity to mediate cell-cell adhesion and matrix modulation in smooth muscle cells. Overall, TCF23 deficiency leads to impaired myometrial remodeling, causing parturition delay and fetal demise. This study sheds light on the critical role of TCF23 as a dowstream mediator of PR in uterine remodeling, reflecting the importance of cell-cell communication and matrix dynamics in myometrial activation and parturition.

Keywords:

• bHLH
• dystocia
• extracellular matrix
• myometrium remodeling
• parturition
• progesterone
• resorption
• smooth muscle cells
• TCF23

Acknowledgments

We are grateful to the Japanese Government (MEXT) Scholarships for the financial support of Fatma M. Minisy during her study at Nagoya City University, Japan.

Author contributions

Methodology, F.M.M., I.S.S. and H.H.S. Software, F.M.M. and H.H.S. Validation, F.M.M. Formal analysis, F.M.M. and T.F. Investigation, F.M.M., A.M.M. and H.H.S. Resources, Y.N. and H.H.S. Data curation, Y.N. and H.H.S. Writing: original draft, F.M.M., and H.H.S. Visualization, F.M.M., R.S. and H.H.S. Supervision, H.H.S., S.S., M.S.O. and H.O. Project administration, H.O. Funding acquisition, H.H.S and H.O. All authors have read and agreed to the published version of the manuscript.

Disclosure statement

No potential conflict of interest was reported by the authors.

Institutional review board statement

The animal study protocol was approved by the Ethics Committee of Nagoya City University (Permit Number: 20–002; Date of approval: April 1, 2020).

Data availability statement

All data generated or analyzed during this study are included in this published article and its supplementary information files. FASTQ files containing the unmapped reads were deposited into NCBI GEO (accession no. GSE236861).

Additional information

Funding

This research was funded by Grants-in-Aid from the Japan Society for the Promotion of Science (JP21K15010 and JP23K05601), and the Hori Sciences and Arts Foundation. Funding agencies had no role in the management, analysis, or interpretation of the data nor were they involved in preparation, review, or approval of the manuscript. The funders were also not involved in the decision to submit the manuscript for publication.