Abstract
An alarming decline in sperm count of men from several countries has become a major concern for the world community. Hormones act on testicular Sertoli cells (Sc) to regulate male fertility by governing the division and differentiation of germ cells (Gc). However, there is a limited knowledge about Sc specific gene(s) regulating the spermatogenic output of the testis. Sclerostin domain-containing 1 protein (Sostdc1) is a dual BMP/Wnt regulator is predominantly expressed in the Sc of infant testes which hardly show any sign of spermatogenesis. In order to investigate the role of Sostdc1 in spermatogenic regulation, we have generated transgenic (Tg) rats which induced persistent expression of Sostdc1 in mature Sc causing reduced sperm counts. Although Sc specific Sostdc1 did not affect the function of either Sc or Leydig cells (Lc) in the adult testis of Tg rat, we observed a selective augmentation of the BMP target genes via activated phospho smad 1/5/8 signaling in Gc leading to apoptosis. Here, for the first time, we have demonstrated that Sostdc1 is a negative regulator of spermatogenesis, and provided substantial evidence that down regulation of Sostdc1 during puberty is critically essential for quantitatively and qualitatively normal spermatogenesis governing male fertility.
Highlights
Spermatogenesis is a complex process occurring inside a specialized microenvironment of testis, where various autocrine, paracrine, and endocrine interactions play an important role[8,9]
We have demonstrated that the persistent expression of Sostdc[1] in adult Sertoli cells (Sc) leads to low sperm count during adulthood indicating that the pubertal down-regulation of Sostdc[1] in Sc plays a critical role in regulating male fertility
We concluded that Sostdc[1] is an essential negative regulator of spermatogenesis based on the following experimental evidences; firstly, Sostdc[1] expression was predominant in immature Sc as compared to that of the maturing Sc
Summary
Spermatogenesis is a complex process occurring inside a specialized microenvironment of testis, where various autocrine, paracrine, and endocrine interactions play an important role[8,9]. Its expression was found to be down-regulated during pubertal maturation of Sc which is associated with robust onset of spermatogenesis Increasing evidences indicate both Wnt and BMP signaling play an essential role in the process of sperm production[19,20,21,22,23]. To delineate any association between the inverse expression of Sostdc[1] and spermatogenic onset, we here have prevented the natural down-regulation of Sostdc[1] expression in pubertal Sc in vivo In this transgenic (Tg) rat model, Sostdc[1] was continued to express in Sc from puberty up to adulthood, which showed an androgen independent, non-obstructive oligozoospermia, and this effect appears to involve the dysregulation of BMP signaling resulting in Gc apoptosis in the Tg testis
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