Ligands, Receptors, and Transcription Factors that Mediate Inter-Cellular and Intra-Cellular Communication during Ovarian Follicle Development


Reliably producing a competent oocyte entails a deeper comprehension of ovarian follicle maturation, a very complex process that includes meiotic maturation of the female gamete, the oocyte, together with the mitotic divisions of the hormone-producing somatic cells. In this report, we investigate murine ovarian folliculogenesis in vivo using publicly available time-series microarrays from primordial to antral stage follicles. Manually curated protein interaction networks were employed to identify autocrine and paracrine signaling between the oocyte and the somatic cells (granulosa and theca cells) at multiple stages of follicle development. We established plausible protein-binding interactions between expressed genes that encode secreted factors and expressed genes that encode cellular receptors. Some computationally identified signaling interactions are well established, such as the paracrine signaling from the oocyte to the somatic cells through the oocyte-secreted growth factor Gdf9, while others are novel connections in term of ovarian folliculogenesis, such as the possible paracrine connection from somatic-secreted factor Ntn3 to the oocyte receptor Neo1. Additionally, we identified several of the likely transcription factors that might control the dynamic transcriptome during ovarian follicle development, noting that the YAP/TAZ signaling pathway is very active in vivo. This novel dynamic model of signaling and regulation can be employed to generate testable hypotheses regarding follicle development that could be validated experimentally, guiding the improvement of culture media to enhance in vitro ovarian follicle maturation and possibly novel therapeutic targets for reproductive diseases.

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We thank Dr. Lei Lei, Sarah Kiesewetter for their invaluable technical support and Dr. Nadereh Jafari, Director of the Genomics Core Facility (Center for Genetic Medicine, Northwestern University) and Dr. Simon Lin and Dr. Gang Feng. Additionally, we would like to thank Dr. Ariella Shikanov and Andrea Jones for their insightful comments and throughout editing this manuscript.


This work has been mainly supported by NIH/NICHD 2 U54 HD041857–07 for study design and collection, analysis and interpretation of the data. BPB was supported NIH/NIGMS 2 T32 GM008449–16.

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BPB designed the computational approached and performed all the computational study. BPB, TKW, LJB and LDS interpreted the results and wrote the manuscript.

Correspondence to Lonnie D. Shea.

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Bernabé, B.P., Woodruff, T., Broadbelt, L.J. et al. Ligands, Receptors, and Transcription Factors that Mediate Inter-Cellular and Intra-Cellular Communication during Ovarian Follicle Development. Reprod. Sci. (2020).

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  • Dynamic signaling
  • Dynamic regulation ovarian follicle development
  • Inter-cellular communication