The Role of microRNAs in Ovarian Granulosa Cells in Health and Disease

Abstract

The granulosa cell (GC) is a critical somatic component of the ovary. It is essential for follicle development by supporting the developing oocyte, proliferating and producing sex steroids and disparate growth factors. Knowledge of the GC's function in normal ovarian development and function, and reproductive disorders, such as polycystic ovary syndrome (PCOS) and premature ovarian failure (POF), is largely acquired through clinical studies and preclinical animal models. Recently, microRNAs have been recognized to play important regulatory roles in GC pathophysiology. Here, we examine the recent findings on the role of miRNAs in the GC, including four related signaling pathways (Transforming growth factor-β pathway, Follicle-stimulating hormones pathway, hormone-related miRNAs, Apoptosis-related pathways) and relevant diseases. Therefore, miRNAs appear to be important regulators of GC function in both physiological and pathological conditions. We suggest that targeting specific microRNAs is a potential therapeutic option for treating ovary-related diseases, such as PCOS, POF, and GCT.

Keywords: GCT; PCOS (polycystic ovary syndrome); POF; granulosa cells; miRNA.

Figure 1

Phenotypes in Dicer KO ovary. Four studies investigate the role of Dicer in GC and ovary. Otsuka et al. (25) use a Dicer hypomorphic mutation mouse. Other three papers [Nagaraja et al. (27), Hong et al. (28), and Lei et al. (29)] show that specific deletion of Dicer in GC hampers the normal function and development of folliculogenesis in ovary.

Figure 2

The interaction between miRNAs and TGFB pathway in GC. The interaction of miRNA-TGFB pathway in GC mainly affects the growth and survival of GC in ovary. FSHR, follicle-stimulating hormone receptor; SMAD3, SMAD family member 3; SMAD4, SMAD family member 4; SMAD7, SMAD family member 7; LOX, lysyl oxidase; RBMS1, RNA-binding morif single-stranded-interacting protein 1. Arrowhead line, promotion; Flat-end line, repression.

Figure 3

The interaction between miRNAs and FSH pathway in GC. The related miRNAs regulate GC proliferation, angiogenesis, hormone secretion and differentiation via interacting with FSH pathway in GC. FSH, Follicle-stimulating hormone; FSHR, Follicle-stimulating hormone receptor; BDNF, Brain-derived neurotrophic factor; KRAS, V-Ki-Ras2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog; Ras, rat sarcoma viral oncogene homolog; LHCGR, luteinizing hormone/chorionic gonadotropin receptor; LRBP, luteinizing hormone receptor mRNA-binding protein. Arrowhead line, promotion; Flat-end line, repression.

Figure 4

The interaction between miRNAs and apoptosis pathway in GC. These miRNA-mRNA communications could greatly modulate GC apoptosis during the process of follicle atresia. MAP3K1, Mitogen-activated protein kinase 1; Klf4, Kruppel-like factor 4; SMAD2, SMAD family member 2; SMAD5, SMAD family member 5; SIRT1, NAD-dependent deacetylase sirtuin-1; IGF1, insulin like growth factor 1. Arrowhead line, promotion; Flat-end line, repression.

Figure 5

The effect of miRNAs on GC from PCOS, POF and GCT. These miRNAs are potential markers or targets for diagnostic, therapeutic, or prognostic treatment of PCOS, POF, or GCT.