Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: Zhu et al. (1998) reported the targeted disruption of the mouse Smad3 gene. Smad3 mutant mice were viable and fertile. Between 4 and 6 months of age, the Smad3 mutant mice became moribund with colorectal adenocarcinomas. The neoplasms penetrated through the intestinal wall and metastasized to lymph nodes. TOmic et al 2004 reported that Ovarian Follicle Development Requires Smad3. Smad3 is an important mediator of the transforming growth factor beta (TGFbeta) signaling pathway. Interestingly, Smad3 deficient (Smad3-/-) mice have reduced fertility compared with wild-type (WT) mice. To better understand the molecular mechanisms underlying the reduced fertility in Smad3-/- animals, this work tested the hypothesis that Smad3 deficiency interferes with three critical aspects of folliculogenesis: growth, atresia, and differentiation. Growth was assessed by comparing the size of follicles, expression of proliferating cell nuclear antigen (PCNA), and expression of cell cycle genes in Smad3-/- and WT mice. Atresia was assessed by comparing the incidence of atresia and expression of Bcl-2 genes involved in cell death and cell survival in Smad3-/- and WT mice. Differentiation was assessed by comparing the expression of FSH receptor (FSHR), estrogen receptor alpha (ERalpha), estrogen receptor beta (ERbeta), and inhibin alpha-, betaA-, and betaB-subunits in Smad3-/- and WT mice. Since growth, atresia, and differentiation are regulated by hormones, estradiol, FSH, and LH (LH) levels were compared in Smad3-/- and WT mice. Moreover, since alterations in folliculogenesis can affect the ability of mice to ovulate, the number of corpora lutea and ovulated eggs in response to gonadotropin treatments were compared in Smad3-/- and WT animals. The results indicate that Smad3 deficiency slows follicle growth, which is characterized by small follicle diameters, low levels of PCNA, and low expression of cell cycle genes (cdk4 and cyclin D2). Smad3 deficiency also causes atretic follicles, degenerated oocyctes, and low expression of bcl-2. Further, Smad3 deficiency affects follicular differentiation as evidenced by decreased expression of ERbeta, increased expression of ERalpha, and decreased expression of inhibin alpha-subunits. Smad3 deficiency causes low estradiol and high FSH levels. Finally, Smad3-/- ovaries have no corpora lutea and they do not ovulate after ovulatory induction with exogenous gonadotropins. Collectively, these data provide the first evidence that reduced fertility in Smad3-/- mice is due to impaired folliculogenesis, associated with altered expression of genes that control cell cycle progression, cell survival, and cell differentiation. The findings that Smad3-/- follicles have impaired growth, increased atresia, and altered differentiation in the presence of high FSH levels, normal expression of FSHR, and lower expression of cyclin D2, suggest a possible interaction between Smad3 and FSH signaling downstream of FSHR in the mouse ovary.

Species: mouse
Mutation name: None
type: null mutation
fertility: infertile - ovarian defect
Comment: A detailed analysis by Tomich et al. (2002) revealed that female mice -/- for Smad 3 are infertile. Whereas mutant mice ovaries appeared the same as wild type at birth, by 7 days after birth and onward less primary and antral follicles could be seen compared to wild type.

Species: mouse
Mutation name: None
type: null mutation
fertility: fertile
Comment: SMAD3 Regulates Gonadal Tumorigenesis. Li Q et al. Inhibin is a secreted tumor suppressor and an activin antagonist. Inhibin alpha null mice develop gonadal sex cord-stromal tumors with 100% penetrance and die of a cachexia-like syndrome due to increased activin signaling. Since SMAD2 and SMAD3 transduce activin signals in vitro, we attempted to define the role of SMAD3 in gonadal tumorigenesis and the wasting syndrome by generating inhibin alpha and Smad3 double mutant mice. Inhibin alpha and Smad3 double homozygous males were protected from early tumorigenesis and the usual weight loss and death. Approximately 90% of these males survived to 26 weeks in contrast to 95% of inhibin-deficient males which develop bilateral testicular tumors and die of the wasting syndrome by 12 weeks. Testicular tumors were either absent or unilaterally slow-growing and less hemorrhagic in the majority of double knockout males. In contrast, development of the ovarian tumors and wasting syndrome was delayed, but still occurred, in the majority of the double-knockout females by 26 weeks. In double mutant females, tumor development was accompanied by typical activin-induced pathological changes. In summary, we identify an important function of SMAD3 in gonadal tumorigenesis in both sexes. However, this effect is significantly more pronounced in the male indicating that SMAD3 is the primary transducer of male gonadal tumorigenesis, while SMAD3 potentially overlaps with SMAD2 function in the ovary. Moreover, the activin-induced cachexia syndrome is potentially mediated through both SMAD2 and SMAD3 or only through SMAD2 in the liver and stomach. These studies identify sexually dimorphic functions of SMAD3 in gonadal tumorigenesis.

Species: mouse
Mutation name: None
type: null mutation
fertility: subfertile
Comment: Redundant Roles of SMAD2 and SMAD3 in Ovarian Granulosa Cells in vivo. Li Q et al. Transforming growth factor beta (TGFbeta) superfamily members are critical in maintaining cell growth and differentiation in the ovary. Although signaling of activins, TGFbetas, growth differentiation factor 9, and nodal converge preferentially to SMAD2 and SMAD3, the in vivo functions and redundancy of these SMADs in the ovary and female reproduction remain largely unidentified. To circumvent the deleterious phenotypic aspects of ubiquitous deletion of Smad2 and Smad3, a conditional knockout strategy was formulated to selectively inactivate Smad2, Smad3, or both Smad2 and Smad3 in ovarian granulosa cells. While granulosa cell ablation of individual Smad2 or Smad3 caused insignificant changes in female fertility, deletion of both Smad2 and Smad3 led to dramatically reduced female fertility and fecundity. These defects were associated with the disruption of multiple ovarian processes including follicular development, ovulation, and cumulus cell expansion. Furthermore, the impaired expansion of cumulus cells may be partially associated with altered cumulus expansion-related transcripts that are regulated by SMAD2/3 signaling. Our results indicate that SMAD2 and SMAD3 function redundantly in vivo to maintain normal female fertility and further support the involvement of an intraovarian SMAD2/3 pathway in mediating oocyte-produced signals essential for coordinating key events of the ovulatory process.

Species: human
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Identification of Common Genetic Variants Influencing Spontaneous Dizygotic Twinning and Female Fertility. Mbarek H et al. (2016) Spontaneous dizygotic (DZ) twinning occurs in 1%-4% of women, with familial clustering and unknown physiological pathways and genetic origin. DZ twinning might index increased fertility and has distinct health implications for mother and child. We performed a GWAS in 1,980 mothers of spontaneous DZ twins and 12,953 control subjects. Findings were replicated in a large Icelandic cohort and tested for association across a broad range of fertility traits in women. Two SNPs were identified (rs11031006 near FSHB, p = 1.54 × 10(-9), and rs17293443 in SMAD3, p = 1.57 × 10(-8)) and replicated (p = 3 × 10(-3) and p = 1.44 × 10(-4), respectively). Based on ∼90,000 births in Iceland, the risk of a mother delivering twins increased by 18% for each copy of allele rs11031006-G and 9% for rs17293443-C. A higher polygenic risk score (PRS) for DZ twinning, calculated based on the results of the DZ twinning GWAS, was significantly associated with DZ twinning in Iceland (p = 0.001). A higher PRS was also associated with having children (p = 0.01), greater lifetime parity (p = 0.03), and earlier age at first child (p = 0.02). Allele rs11031006-G was associated with higher serum FSH levels, earlier age at menarche, earlier age at first child, higher lifetime parity, lower PCOS risk, and earlier age at menopause. Conversely, rs17293443-C was associated with later age at last child. We identified robust genetic risk variants for DZ twinning: one near FSHB and a second within SMAD3, the product of which plays an important role in gonadal responsiveness to FSH. These loci contribute to crucial aspects of reproductive capacity and health.//////////////////