Structural and Functional Modifications of Sertoli Cells in the Testis of Adult Follicle-Stimulating Hormone Receptor Knockout Mice1

Abstract

Follicle stimulating hormone (FSH) plays important roles during testicular development and in the maintenance of spermatogenesis in the adult. However, the cellular events or pathways that FSH regulates to achieve these effects in Sertoli cells, where the FSH receptors (FSH-R) are located, is still not fully elucidated. The development of FSH-R knockout (FORKO) mice provides a model to examine alterations in testicular structure and function in its absence. To this end, light (LM) and electron microscopic (EM) analyses of perfusion-fixed testes of wild-type and FORKO mice of different ages were performed. Under the LM, a significant reduction was noted in the profile area of seminiferous tubules of FORKO mice compared with their wild-type counterparts at different ages. In addition, FORKO testes revealed large irregularly shaped spaces within the seminiferous epithelium, extending from the base to the lumen. Such spaces were often separated by anastomotic cords of spherical germ cells or completely surrounded elongating spermatids. This phenotype was restricted to half or less of the circumference of only some tubules, but was seen at all stages. EM analyses revealed that the spaces corresponded to an apparent accumulation of fluid in the Sertoli cell cytoplasm, coincident with an absence of the fine flocculent ground substance seen in wild-type mice. However, the Sertoli organelles, while less prominent, appeared intact and to be floating in the enlarged fluid-filled cytoplasm. Functionally, androgen-binding protein (ABP), a major secretory protein of Sertoli cells, was dramatically reduced in FORKO mice. These results suggest that FSH-R signaling normally maintains water balance in Sertoli cells in addition to regulating ABP production.

FSH regulates the formation of adherens junctions and ectoplasmic specialisations between rat Sertoli cells in vitro and in vivo

“…Despite the fact that various roles for FSH in the seminiferous epithelium are emerging (see Allan & Handelsman (2005) and O'Donnell et al (2005)), reports on interSertoli cell junctions in various transgenic models of FSH, LH and androgen action deficiency are limited. However, ultrastructural studies in FSH receptor-deficient (FORKO) mice show various defects in Sertoli cell ultrastructure, particularly fluid-filled cytoplasm indicative of disturbed fluid dynamics (Grover et al 2004). Although ES structures were observed in FORKO mice, some abnormalities were noted, including dilated endoplasmic reticulum associated with ES (Grover et al 2004).…”

“…Transgenic male mice with targeted disruption of the FSH gene are fertile (Kumar et al 1997), while male mice lacking a functional FSH receptor show some impairment of fertility (Dierich et al 1998, Krishnamurthy et al 2000. However, a closer examination of the phenotypes of these mice revealed defects in the ability of Sertoli cells to support germ cells in FSH -null mice (Wreford et al 2001) and defects to germ cells, such as elongated spermatids (Krishnamurthy et al 2000) and Sertoli cells (Grover et al 2004), in FSH receptor-null mice. Further support for a role for FSH in spermatogenesis comes from a study demonstrating that short-term (1-week) passive immunoneutralisation of circulating FSH in normal rats decreased germ cell numbers and increased germ cell apoptosis in a setting of normal serum and testicular testosterone (Meachem et al 1999).…”

Mutation of the Follicle-Stimulating Hormone Receptor Gene 5′-Untranslated Region Associated With Female Hypertension

“…[11][12][13] They also exhibit the same changes seen in postmenopausal women, such as osteoporosis, hypercholesterolemia, and weight gains. In 2003, Javeshghani et al 14 reported that these mice have increased blood pressure, indicating that there is vascular remodeling.…”

Molecular mechanisms by which hormones and cytokines regulate cell junction dynamics in the testis

“…For instance, male mice lacking a functional FSH receptor had impaired fertility and defected elongated spermatids and Sertoli cells (Krishnamurthy et al 2000, Grover et al 2004. The expression of FSH receptors on Sertoli cells in adult rats is also stage-specific, being the highest at stages IX and X (Kliesch et al 1992).…”