Expression Patterns and Regulatory Functions of MicroRNAs During the Initiation of Primordial Follicle Development in the Neonatal Mouse Ovary1

Abstract

The initiation of primordial follicle development is essential for female fertility, but the signals that trigger this process are poorly understood. Given the potentially important roles of microRNAs (miRNAs) in the ovary, we aimed to study the expression patterns and regulatory functions of miRNAs during the initiation of primordial follicle development. Expression patterns of miRNA in the neonatal mouse ovary were profiled by microarray, and 24 miRNAs whose abundances differed significantly between ovaries from 3- and 5-day-old mice were identified. Pathway enrichment analysis revealed that 48 signal transduction pathways are modulated by the up-regulated miRNAs and 29 pathways are modulated by the down-regulated miRNAs (P-value and false discovery rate < 0.001). A miRNA-mRNA regulatory network was established for TGF-beta signaling pathway-related genes. Among the miRNAs involved in this pathway, miR-145 was chosen for further analysis. Down-regulation of miR-145 using an antagomir (AT) decreased the proportion and number of the primordial follicles and increased that of the growing follicles in the cultured ovaries (P < 0.05). The mean oocyte diameter in the primordial follicles was significantly greater in the AT group relative to the AT-negative control group (P < 0.05), whereas the mean oocyte diameter in growing follicles was smaller in the AT group than in the AT-negative control group. In addition, we confirmed that miR-145 targets Tgfbr2. The miR-145 AT caused an increase in TGFBR2 expression and activation of Smad signaling but did not affect the p38 MAPK or JNK pathway. These data suggest that miRNAs and the signaling pathways they modulate are involved in the initiation of primordial follicle development, and miR-145 targets Tgfbr2 to regulate the initiation of primordial follicle development and maintain primordial follicle quiescence.

MALAT1 Modulates TGF-β1-Induced Endothelial-to-Mesenchymal Transition through Downregulation of miR-145

“…MiR-145 has been reported to negatively regulate TGF-β signaling by directly targeting SMAD3 and TGFBR2 [19-22, 24]. We thought that this might be the mechanisms by which miR-145 inhibits TGF-β1-induced EndMT.…”

“…Furthermore, miR-145 has been reported to directly target TGF-β receptor type 2 (TGFBR2) [23]. Downregulation of miR-145 using an antagomir caused an increase in TGFBR2 expression and activation of SMAD3 [24]. Based on these findings, we speculated that miR-145 might play a significant regulatory role in EndMT by simultaneously targeting TGFBR2 and SMAD3.…”

The protective effects of human umbilical cord mesenchymal stem cells on damaged ovarian function: A comparative study

“…Real-time PCR was performed using the AB StepOne Plus PCR machine (Applied Biosystems, Foster City, CA, USA) as described in a previous study (37). The PCR amplification of all transcripts was performed with the gene-specific primers listed in Table 1.…”

A Role of MicroRNAs in Cell Differentiation During Gonad Development

“…Yang et al (2013b) showed that 24 miRNAs are differentially expressed in mouse ovaries during the developmental period of primordial follicles into primary follicles. Whereas some miRNAs were downregulated, others were upregulated, implying they might have a role in maintaining the dormancy of primordial follicles or in initiating their development.…”

“…Whereas some miRNAs were downregulated, others were upregulated, implying they might have a role in maintaining the dormancy of primordial follicles or in initiating their development. Gene ontology analysis revealed many signaling pathways that are modulated by these differentially expressed miRNAs (Yang et al 2013b); many of these signaling pathways are involved in initiation of primordial follicle development (Skinner 2005). The upregulated miR-145 is predominantly expressed in granulosa cells of primary follicles and is undetectable in pre-granulosa cells of primordial follicles (Yang et al 2013b).…”