The PDGF signaling pathway controls multiple steroid-producing lineages

Abstract

The platelet-derived growth factor (PDGF) signaling pathway regulates numerous lineages of mesenchymal cell origin during development and in the adult. The transcriptional targets of this pathway have been shown to be required in several PDGF-dependent processes, but the roles of these targets in specific tissues is just beginning to be identified. In this study, we show that five different PDGF target genes are essential for male and/or female fertility. Mutations in each of these five different genes lead to defects in the steroid-producing cells in the testis and/or ovary and altered hormone production, suggesting that the PDGF pathway controls steroidogenesis through these genes in both sexes. Furthermore, conditional mutations of both PDGF receptors revealed a requirement in steroid-producing cells in multiple organs, including the testis, ovary, and adrenal cortex. Therefore, PDGF signaling may constitute a common mechanism in the control of multiple steroidogenic lineages.[Keywords: PDGF; testis; ovary; steroid hormone; Leydig cell; theca cell] Supplemental material is available at http://www.genesdev.org. Steroidogenesis and the development of the steroid-producing cells in the gonads is a tightly controlled process in both sexes, requiring regulation at many stages of development through endocrine, autocrine, and paracrine mechanisms. Defects in these processes lead to infertility, malformation of the reproductive tracts, and abnormal secondary sexual characteristics. In males, low testosterone production leads to abnormalities in spermatogenesis, undescended testes, ambiguous genitalia, and infertility (Habert et al. 2001). In females, the production of estrogen and progesterone is essential for ovulation and the maintenance of pregnancy (Fisher et al. 1998;Toda et al. 2001). Altered levels of steroid hormones are known to be associated with many of the common types of infertility in both men and women, such as hypogonadism and Polycystic Ovary Syndrome (PCOS), yet many of the mechanisms that control steroidogenic cell development and hormone production are not well understood.In the gonads, steroid hormones are synthesized by specialized endocrine cells: the Leydig cells in the testis (Habert et al. 2001) and theca cells in the ovary (Magoffin 2005). In the testis, Leydig cells have at least two clearly defined waves of development, as fetal and adult Leydig cells. Fetal Leydig cells appear very early after sex determination, by embryonic day 12.5 (E12.5) in the mouse, and testosterone production from these cells is necessary for the masculinization of the fetus. Postnatally, fetal Leydig cells are replaced by adult Leydig cells, which are required for the progression and maintenance of spermatogenesis. In the ovary, the production of steroid hormones requires cooperation between two cell types, the theca and granulosa cells (Magoffin 2005). Theca cells are steroidogenic, as they initiate steroid synthesis by importing cholesterol to the mitochondrial membrane and synthesize steroid hormones de novo. ...

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