Numerous genes encoding proteins contributing to the integrity of the BTB have been found to be mis-regulated in SCARKO mice including Claudin 3, Claudin-11, Occludin, Gelsolin, Cadherin 2, Espin and Jam 3 40, 87, In addition, there are changes in expression and localization of several PTM proteins such as the intermediate filament desmin and basement membrane protein laminin. As a result, voltage dependent L-type Ca2+ channels open allowing the influx of Ca2+, which can alter many cellular processes.
Thus, it is imperative to investigate the factors that are involved in transition of Sertoli cells from proliferation to maturation phase. FSH and cAMP likely act through GEFs to activate PI3-K and then phosphoinositide dependent protein kinase (PDK1) and PKB in Sertoli cells. During puberty, FSH activates the MAP kinase cascade and ERK kinase in Sertoli cells most likely via cAMP interactions with guanine nucleotide exchange factors (GEFs) and activation of Ras-like G proteins. FSH also causes Ca2+ influx into Sertoli cells that is mediated by cAMP and perhaps PKA modification of surface Ca2+ channels. Taking consideration of all these studies, a comprehensive diagram explaining the role of FSH and other factors in Sertoli cell proliferation can be proposed (27) (Figure 3).
In three initial Sertoli cell specific AR knock out mice (SCARKO) models 44, 45, 48, the number of Sertoli cells was normal and the cells underwent appropriate maturation with the correct timing during puberty. In agreement with this idea, AR was not eliminated in all Leydig cells and AR was lost in some Sertoli cells of the LC-ARKO mice. Circulating testosterone concentrations in PTM-ARKO mice are within the normal range, but only because of increased LH input. PTM-ARKO mice have normal numbers of adult Leydig cells but, there are also significant numbers of precursor Leydig cells present in adult mice 77, 78.
However, there are controversies about the influence that estrogens can have on the development of RA. Moreover, simultaneous treatment with bromocriptine, a dopamine agonist, reduces manifestations of SLE (induced by PRL or estrogen), such as anti-DNA antibody production and mortality (149–151). Epigenetically, estrogens (ERαs) reverse the protection of the MRL/Faslpr/lpr strain mediated by histone deacetylase inhibitors (HDIs) and short-chain fatty acids (SCFAs) in vivo, which reduce skin lesions and the production of anti-dsDNA IgG2a. PRL promotes immature B-cell survival through the activation of STAT3, which binds to the promoters of the antiapoptotic Birc5, Bcl2a1a and Bcl2l2 genes (139, 140). Even in MRL/Faslpr/lpr mice, which also develop SLE-like disease, estrogens increase immune complex-mediated glomerulonephritis (IgG1, IgG2a, IgG3, IgM; anti-dsDNA), lymphoproliferation, and mortality (134–136). In humans, PRL increases the production of IgA, IgM, and IgG in the PBMCs of healthy individuals and, to a greater extent, in patients with SLE, as well as the synthesis of anti-dsDNA IgG in vitro (127, 128).
The significant finding that emerged from T supplementation studies was that Sertoli cells internalized steroidal molecules from the peripheral circulation. ESR1 agonist reduced the sperm counts, evaluated by flow cytometry of testicular cells, through suppression of plasmatic gonadotropins and testosterone. Testosterone RIAs demonstrated that tamoxifen treatment reduced the levels of intratesticular androgens in adult male rat concomitant with a reduction in their siring ability . Notably, the mechanism through which T brings about the stage-specific differentiation of germ cells lacking Androgen Receptors (AR). All these hormones and factors have been implicated in various stages of Sertoli cell development and their balanced action of mechanism is mandatory for ensuring accurate Sertoli cell number, establishment of BTB and maintaining spermatogenesis. The functional role of RA was verified by generating vitamin A-deficient (VAD) mice that were infertile due to spermatogonia differentiation arrest at the Aaligned stage and treating them with RA results in the complete recovery of spermatogenesis (157). Retinoic acid (biologically active component of vitamin A) is a major factor that control the complex process of spermatogenesis and is also important driven force of Sertoli cell development (155).
For example, transcription factors including Krüppel-like factor 4 (KLF4) , nuclear factor (NF)-κB , and activator protein-1 (AP-1) are involved in the regulation of Sertoli cell differentiation by FSH. Furthermore, FSH targets functional factors and transcription factors through the cAMP/PKA pathway to affect Sertoli cell differentiation and apoptosis 76,77. The suppression of FSH in neonates reduces the number of final Sertoli cells by approximately 40% , which in turn affects the quantity of sperm. FSH-induced signal transduction is mediated by FSHR, and its function reliant on interactions with numerous intracellular effectors. Interestingly, the role of androgens in establishing normal reproductive tract development and the masculinization of anogenital distance (AGD) is limited to a specific developmental window, known as the "masculinization programming window" (MPW).