Connective Tissue Growth Factor Is Required for Normal Follicle Development and Ovulation

Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas 77030, USA.
Molecular Endocrinology (Impact Factor: 4.02). 08/2011; 25(10):1740-59. DOI: 10.1210/me.2011-1045
Source: PubMed


Connective tissue growth factor (CTGF) is a cysteine-rich protein the synthesis and secretion of which are hypothesized to be selectively regulated by activins and other members of the TGF-β superfamily. To investigate the in vivo roles of CTGF in female reproduction, we generated Ctgf ovarian and uterine conditional knockout (cKO) mice. Ctgf cKO mice exhibit severe subfertility and multiple reproductive defects including disrupted follicle development, decreased ovulation rates, increased numbers of corpus luteum, and smaller but functionally normal uterine horns. Steroidogenesis is disrupted in the Ctgf cKO mice, leading to increased levels of serum progesterone. We show that disrupted follicle development is accompanied by a significant increase in granulosa cell apoptosis. Moreover, despite normal cumulus expansion, Ctgf cKO mice exhibit a significant decrease in oocytes ovulated, likely due to impaired ovulatory process. During analyses of mRNA expression, we discovered that Ctgf cKO granulosa cells show gene expression changes similar to our previously reported granulosa cell-specific knockouts of activin and Smad4, the common TGF-β family intracellular signaling protein. We also discovered a significant down-regulation of Adamts1, a progesterone-regulated gene that is critical for the remodeling of extracellular matrix surrounding granulosa cells of preovulatory follicles. These findings demonstrate that CTGF is a downstream mediator in TGF-β and progesterone signaling cascades and is necessary for normal follicle development and ovulation.

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    • "The different stages in follicle development are characterized by specific molecular markers and hormonal profiles which differentiate early antral from pre-ovulatory and luteinized follicles. The gene expression profile of the early antral follicle typically shows low levels of follicle stimulating hormone receptor (FSHR) (Abdennebi et al., 1999; Camp et al., 1991; O'Shaughnessy et al., 1996; Weil et al., 1999), luteinizing hormone/choriogonadotrophin receptor (LHCGR) (Abdennebi et al., 1999; Camp et al., 1991), cholesterol side-chain cleavage enzyme (CYP11A1) (Oonk et al., 1990), aromatase (CYP19A1), amphiregulin (AREG) and epiregulin (EREG), (Ashkenazi et al., 2005; Zamah et al., 2010), whereas progression to the pre-ovulatory follicle consequent upon an increase in FSH secretion, results in an increase in FSHR and LHCGR (Ashkenazi et al., 2005; Zamah et al., 2010) along with concomitant increases in CYP11A1 (Oonk et al., 1990) and CYP19A1 (Clement and Monniaux, 2012; Fitzpatrick et al., 1997; Kawai et al., 2012; Nagashima et al., 2011) expression in preparation for the LH surge (Camp et al., 1991; Hillier, 2001; Hsueh et al., 2000). Following luteinization, the genetic profile shifts to AREG and EREG translation promoting progesterone synthesis and secretion, resulting in ovulation (Zamah et al., 2010; Clement and Monniaux, 2012; Conti et al., 2006; Su et al., 2010). "
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    • "Recent studies have shown that the morphological and genetic transition from the primordial follicle stage through to ovulation and corpus luteum formation is associated with the activation of a growth factor signalling cascade that highly regulates the proliferation and differentiation of ovarian cells (Figure 1), (Nagashima et al. 2011; Joseph et al. 2012; Kawano et al. 2012). The most important growth factors include genes of the TGFB superfamily that are expressed in mammalian ovarian somatic cells and in oocytes in a stagespecific manner, and thereby, function as intraovarian regulators of folliculogenesis (Paradis et al. 2009; Nagashima et al. 2011; Corduk et al. 2012). The most important TGFB superfamily genes include bone morphogenic proteins 2, 4, 5, 6, 7, and 15 (BMP2, BMP4, BMP5, BMP6, BMP7, and BMP15) and growth differentiation factor 9 (GDF9), which are expressed throughout folliculogenesis and regulate key steps of follicle growth and development (Figure 2), (Knight and Glister 2006). "
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