GATA4 Deficiency Impairs Ovarian Function in Adult Mice1

Abstract

Transcription factor GATA4 is expressed in granulosa cells and, to a lesser extent, in other ovarian cell types. Studies of mutant mice have shown that interactions between GATA4 and its cofactor, ZFPM2 (also termed FOG2), are required for proper development of the fetal ovary. The role of GATA4 in postnatal ovarian function, however, has remained unclear, in part because of prenatal lethality of homozygous mutations in the Gata4 gene in mice. To circumvent this limitation, we studied ovarian function in two genetically engineered mouse lines: C57BL/6 (B6) female mice heterozygous for a Gata4-null allele, and 129;B6 female mice in which Gata4 is deleted specifically in proliferating granulosa cells using the Cre-loxP recombination system and Amhr2-cre. Female B6 Gata4(+/-) mice had delayed puberty but normal estrous cycle lengths and litter size. Compared to wild-type mice, the ovaries of gonadotropin-stimulated B6 Gata4(+/-) mice were significantly smaller, released fewer oocytes, produced less estrogen, and expressed less mRNA for the putative GATA4 target genes Star, Cyp11a1, and Cyp19. Gata4 conditional knockout (cKO) mice had a more severe phenotype, including impaired fertility and cystic ovarian changes. Like Gata4(+/-) mice, the ovaries of gonadotropin-stimulated cKO mice released fewer oocytes and expressed less Cyp19 than those of control mice. Our findings, coupled with those of other investigators, support the premise that GATA4 is a key transcriptional regulator of ovarian somatic cell function in both fetal and adult mice.

The transcription factor GATA4 is required for follicular development and normal ovarian function

“…Recently, Bennett et al (2012) and Kyrönlahti et al (2011) deleted Gata4 in proliferating granulosa cells using Cyp19 - or Amhr2-Cre , respectively (the recombination mediated by these Cre drivers is inefficient within the ovary until after birth) (Bennett et al, 2012; Kyrönlahti et al, 2011). Intriguingly, the Amhr2Cre; Gata4 floxed/floxed adult ovaries had a similar phenotype to the Sf1Cre; Gata4 floxed/floxed ovaries with cyst formation and other reproductive defects such as impaired fertility (Kyrönlahti et al, 2011).…”

Transgenic mouse models in the study of reproduction: insights into GATA protein function

“…However, all mutant mice had an abnormal response to exogenous gonadotropins and the presence of ovarian cysts was frequently observed (Kyrönlahti et al 2011b, Bennett et al 2012, Efimenko et al 2013. In all cases, mutant females were either sub-fertile or infertile.…”

“…The authors indicated that the activity of Cre recombinase was detected in the Müllerian duct mesenchyme and female gonads as early as E12.5 using the ROSA26 flox-stop-flox lacZ reporter (R26R) mice. Transgenic mouse models in the study of reproduction R7 mice (Kyrönlahti et al 2011b). While ovarian development appeared overtly normal in young animals, the authors noted impaired fertility and cystic ovarian changes in aged females.…”

Simultaneous Gene Deletion of Gata4 and Gata6 Leads to Early Disruption of Follicular Development and Germ Cell Loss in the Murine Ovary1

“…Other promoters such as Anti-Müllerian hormone (Amh), Sf1, inhibinα and steroidogenic acute regulatory protein (Star) also contain the consensus GATA-binding sequence and are activated by GATA4 [7,12] The importance of GATA4 in ovarian development and function has been highlighted recently. Depending upon the type of promoter driving the Cre-Lox recombination system (Amhr2, Cyp19 or Sf1-Cre), the loss of Gata4 expression within the ovary produced either subfertile or infertile animals [8,13,14]. The degree of disruption in follicular development and of formation of ovarian cystic structures varied depending on the Cre recombinase, but regardless of the system used, conditional mutant females showed an aberrant response to exogenous gonadotropins [8,13,14].…”

“…Depending upon the type of promoter driving the Cre-Lox recombination system (Amhr2, Cyp19 or Sf1-Cre), the loss of Gata4 expression within the ovary produced either subfertile or infertile animals [8,13,14]. The degree of disruption in follicular development and of formation of ovarian cystic structures varied depending on the Cre recombinase, but regardless of the system used, conditional mutant females showed an aberrant response to exogenous gonadotropins [8,13,14]. The differences found among these transgenic models can be explained by the timing of Cre-recombination (Sf1-Cre is activated embryonically while Cyp19-and Amhr2-Cre act postnatally).…”