Biomechanics and mechanical signaling in the ovary: a systematic review

Abstract

Purpose: Mammalian oogenesis and folliculogenesis share a dynamic connection that is critical for gamete development. For maintenance of quiescence or follicular activation, follicles must respond to soluble signals (growth factors and hormones) and physical stresses, including mechanical forces and osmotic shifts. Likewise, mechanical processes are involved in cortical tension and cell polarity in oocytes. Our objective was to examine the contribution and influence of biomechanical signaling in female mammalian gametogenesis.

Methods: We performed a systematic review to assess and summarize the effects of mechanical signaling and mechanotransduction in oocyte maturation and folliculogenesis and to explore possible clinical applications. The review identified 2568 publications of which 122 met the inclusion criteria.

Results: The integration of mechanical and cell signaling pathways in gametogenesis is complex. Follicular activation or quiescence are influenced by mechanical signaling through the Hippo and Akt pathways involving the yes-associated protein (YAP), transcriptional coactivator with PDZ-binding motif (TAZ), phosphatase and tensin homolog deleted from chromosome 10 (PTEN) gene, the mammalian target of rapamycin (mTOR), and forkhead box O3 (FOXO3) gene.

Conclusions: There is overwhelming evidence that mechanical signaling plays a crucial role in development of the ovary, follicle, and oocyte throughout gametogenesis. Emerging data suggest the complexities of mechanotransduction and the biomechanics of oocytes and follicles are integral to understanding of primary ovarian insufficiency, ovarian aging, polycystic ovary syndrome, and applications of fertility preservation.

Keywords: Folliculogenesis; Mechanical signaling; Mechanotransduction; Oocyte maturation; Ovarian biomechanics.

Fig. 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analysis) diagram of search results and article flow

Fig. 2

Maintenance of a quiescent primordial follicle is regulated by Hippo and Akt signaling. The Hippo signaling pathway inhibits primordial follicle activation. Cells probe the rigidity of their microenvironment and respond through central regulators of intracellular contractility (e.g., Rho GTPase and Rho-associated protein kinase (ROCK)). (A) An increase in internal stress from environmental rigidity (lightning bolt) is likely mechanically mediated through actin by negative growth factors (i.e., macrophage stimulating (MST1/2), salvador 1 (SAV1), and large tumor-suppressor homolog (LATS1/2)) that signals to the cell via Rho GTPase and ROCK phosphorylation of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ), (B) inhibiting it from crossing to the nucleus to bind to promoter regions on the DNA to promote transcription of growth stimulators. Thus, the Hippo signaling pathway appears to utilize internal mechanical stress and associated mechanical signaling to maintain the follicle in a quiescent state and inhibit follicular activation. (C) Phosphatase and tensin homolog deleted from chromosome 10 (PTEN) dephosphorylates activated phosphatidylinositol-3,4,5-triphosphate (PIP3) to phosphatidylinositol-4,5-bisphosphate (PIP2) preventing follicular activation by counteracting the Akt (protein kinase B) pathway and allowing forkhead box O3 (FOXO3) transcription factor, an essential regulator of follicular quiescence, to maintain the latency period of the follicle. The red arrows indicate pathways that are likely active to maintain follicle latency while gray arrows signify non-active steps. PI3K, phosphatidylinositol 3-kinase; PDK1, 3-phosphoinositide-dependent protein kinase-1 *SUN1/2, transmembrane proteins; Nesprin, nuclear envelope spectrin repeat protein.

Fig. 3

Activation of a primordial follicle is regulated by Hippo and Akt signaling. (A) Fragmentation force is likely transmitted through actin to activate the Hippo signaling pathway via Rho GTPase and Rho-associated protein kinase (ROCK). (B) This leads to a dephosphorylated yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) which enables entry into the nucleus. (C) Simultaneously, the Akt (protein kinase B) pathway is also activated by the phosphorylation of phosphatidylinositol-4,5-bisphosphate (PIP2) to phosphatidylinositol-3,4,5-triphosphate (PIP3) that subsequently leads to Akt phosphorylation allowing it to enter the nucleus. (D) Upon entry, the forkhead box O3 (FOXO3) transcription factor, an essential mediator of follicle dormancy, is phosphorylated at the Akt site causing nuclear export into the cytoplasm. (E) The nuclear YAP/TAZ binds the transcriptional enhancer associate domain (TEAD) allowing for expression of growth factors (i.e., cysteine-rich protein 61 (CYR61/CCN1), connective tissue growth factor (CTGF/CCN2), and nephroblastoma overexpressed (NOV/CCN3)) and baculoviral inhibitors of apoptosis repeat containing (BIRC) proteins. CCN and BIRC are growth factors that lead to follicular activation and cell growth. The red arrows indicate pathways that are likely active to activate the follicle while gray arrows signify non-active steps. PI3K, phosphatidylinositol 3-kinase; PDK1, 3-phosphoinositide-dependent protein kinase-1; MST1/2, macrophage stimulating; SAV1, salvador 1; LATS1/2, large tumor-suppressor homolog *SUN1/2, transmembrane proteins; Nesprin, nuclear envelope spectrin repeat protein.

Fig. 4

Different concentrations of key effectors of the Hippo and Akt pathways. In the quiescent state, the Akt (protein kinase B) pathway can keep forkhead box O3 (FOXO3) unphosphorylated preventing follicular activation. In the Hippo pathway, yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are phosphorylated keeping them from relocating to the nucleus thereby preventing activation. In contrast, in an activated follicle, there will be a higher concentration of phosphorylated FOXO3 causing it to leave the nucleus and enabling follicular activation. In addition, more YAP/TAZ will be in an unphosphorylated state. When the follicle senses mechanical disruption, globular actin (G-actin) is polymerized to filamentous actin (F-actin) which is also associated with follicular activation

Fig. 5

Cortical tension and polarity facilitators of meiosis for polar body emission. (A) Asymmetric division during cytokinesis of mammalian female meiosis requires a gradient of cortical tension to eject the first polar body. (B) The radius of an oocyte (R1) in comparison to the radius of the polar body (R2) demonstrates an asymmetric division. Hooke’s Law describes the cleavage force is proportional to the surface tension or membrane stiffness. The cortical tension of the oocyte (T1) and the polar body (T2) demonstrates the creation of a microdomain, a specialized area of the cell membrane, for sequestration and completion of meiosis I. (C) The mechanical polarity is contributed by actin and myosin II, which are mechanically sensitive and congregate in areas of high cortical tension (i.e., amicrovillar domain) and by the ezrin–radixin–moesin (ERM) proteins in areas of lower cortical tension (i.e., microvillar domain). Rac, a Rho GTPase, accumulates by polarization in the cortex overlying the spindle, which creates spindle stability and facilitates the release of the polar body. These all contribute to creating a tension gradient allowing for a contraction on the polar body to pull away and overcome the inward forces