Gonadal differentiation, sex determination and normalSryexpression in mice require direct interaction between transcription partners GATA4 and FOG2

Abstract

In mammals, Sry expression in the bipotential, undifferentiated gonad directs the support cell precursors to differentiate as Sertoli cells, thus initiating the testis differentiation pathway. In the absence of Sry, or if Sry is expressed at insufficient levels, the support cell precursors differentiate as granulosa cells, thus initiating the ovarian pathway. The molecular mechanisms upstream and downstream of Sry are not well understood. We demonstrate that the transcription factor GATA4 and its co-factor FOG2 are required for gonadal differentiation. Mouse fetuses homozygous for a null allele of Fog2 or homozygous for a targeted mutation in Gata4 (Gata4ki) that abrogates the interaction of GATA4 with FOG co-factors exhibit abnormalities in gonadogenesis. We found that Sry transcript levels were significantly reduced in XY Fog2–/– gonads at E11.5, which is the time when Sry expression normally reaches its peak. In addition, three genes crucial for normal Sertoli cell function (Sox9, Mis and Dhh) and three Leydig cell steroid biosynthetic enzymes (p450scc, 3βHSD and p450c17) were not expressed in XY Fog2–/– and Gataki/ki gonads, whereas Wnt4, a gene required for normal ovarian development, was expressed ectopically. By contrast, Wt1 and Sf1, which are expressed prior to Sry and necessary for gonad development in both sexes, were expressed normally in both types of mutant XY gonads. These results indicate that GATA4 and FOG2 and their physical interaction are required for normal gonadal development.

Integrated analysis of miRNA and mRNA expression profiles in development of porcine testes

“…In addition, the physical interaction between the transcription factor GATA4 and its co-factor FOG2 are required for normal gonadal development through regulating the normal expression of Sox9 and Sry. 40,41 The signals that come from the transforming growth factor b (TGF-b) superfamily of proteins play critical roles governing the testis development and spermatogenesis. 42 In our study, several members of TGF-b superfamily genes were detected in the differentially-expressed gene analysis between samples, such as TGF-b1, TGF-b2, TGF-b3, TGF-bR3, BMP and BMP6.…”

Insights Into the Roles of GATA Factors in Mammalian Testis Development and the Control of Fetal Testis Gene Expression

“…GATA4 initiates testis differentiation by regulating at least two genes: Sex determining region Y chromosome ( Sry ) and Sry-related homeobox gene 9 ( Sox9 ); both genes are markedly downregulated in newly differentiated testes that lack a fully functional GATA4 protein ( 41 – 43 ). However, as for many of the proposed GATA target genes in the testis, it remains to be seen whether they are indeed direct targets.…”

“…The requirement for GATA4 in Sry and Sox9 transcription has raised the important question as to whether it also participates in the specification of the Sertoli cell lineage at the time of sex determination. Mice lacking a functional GATA4 protein that can no longer interact with FOG2 do not express any Sertoli cell markers ( 41 ), indicating that the GATA4-FOG2 complex (and by extension GATA4 itself) is required for the differentiation of pre-Sertoli cells. Additional insights have come from studies that have reprogrammed fibroblasts into embryonic Sertoli cells.…”

Sertoli Cell-Germ Cell Interactions Within the Niche: Paracrine and Juxtacrine Molecular Communications

“…In 2015, Chen and colleagues demonstrated that targeted loss of Gata4, a known Sertoli cell marker also involved in mouse genital ridge initiation, sex determination, and embryonic testis development (72)(73)(74), resulted in a loss of the establishment and maintenance of the SSC pool, and led to Sertoli cell-only syndrome (41). Loss of Gata4 altered the expression of a number of chemokines, including Cxcl12 (SFD1, binding to the CXCR4 receptor) and Ccl3 (binding to the CCR1 receptor), which are known to guide pro-spermatogonia toward the basement membrane and the niche provided by Sertoli cells (39,40).…”