Abstract
Testicular Sertoli cells (Sc) are main somatic component of seminiferous tubules that govern the differentiation of germ cells (Gc) and provide them physical support. Sc are the target of follicle stimulating hormone (FSH) and testosterone (T) which are known to regulate spermatogenesis. FSH and T levels in human and sub-human male primates remain high during infancy (4–6 months post birth), similar to those during puberty. Subsequently, juvenile phase is marked with low levels of these hormones. In spite of prolonged hormonal exposure, spermatogenesis is not discerned during infancy unlike that during puberty. Situation during infancy is similar to certain idiopathic male infertility, where prolonged hormone supplementation fails to initiate spermatogenesis. In our quest to determine non hormonal causes of idiopathic infertility which may reside within the Sc, we investigated the association between spermatogenesis and Sc specific gene(s) expressed differentially during puberty and infancy. Although products of several genes may be necessary for quantitatively normal spermatogenesis, one needs to investigate their roles one by one. Differential display and real time PCR analysis revealed higher expression of a known tumor suppressor, Dickkopf homolog 3 (DKK3), by pubertal monkey Sc as compared to infant Sc. To evaluate role of DKK3 in spermatogenesis, we generated DKK3 knock down mice (DKDM) using shRNA construct targeted to DKK3. In testis of adult DKDM, expression of DKK3 mRNA and protein were significantly (p<0.05) low and was associated with elevated WNT-4/β-CATENIN activity. Elevated β-CATENIN activity is known to restrict Sc maturation. Abundant expression of infant Sc marker, Mullerian inhibiting substance (MIS), in the testes of adult DKDM confirmed lack of Sc maturation in DKDM. Gc differentiation and fertility was severely compromised in DKDM. This is the first report of role of DKK3 in the testis and DKK3 mediated regulation of spermatogenesis via WNT-4/β-CATENIN modulation.
Highlights
Sertoli cells (Sc) are the main somatic cells of testis which play a major role in cyto-architectural organization of the seminiferous tubule and most importantly, govern the differentiation of germ cells (Gc)
T levels in such monkeys were increased by 6–10 fold, testicular weight were increased by 5–6 fold and markers of initiation of spermatogenesis such as enlarged seminiferous tubules containing large populations of spermatogonia B and primary spermatocytes were evident (Fig. 1A and B) like those during puberty [26]
Sc cultured from 20 day old mice showed significantly (p,0.05) higher expression of Dickkopf homolog 3 (DKK3) mRNA as compared to Sc from 7 day old mice (Fig. 1D)
Summary
Sertoli cells (Sc) are the main somatic cells of testis which play a major role in cyto-architectural organization of the seminiferous tubule and most importantly, govern the differentiation of germ cells (Gc). Hormonal causes of male infertility are well known, lack of sufficient knowledge about intracellular mechanisms leading to the production of important Sc factors necessary for regulating spermatogenesis is the main reason behind inability to diagnose and treat certain forms of idiopathic infertility. Testicular Sc bear receptors for FSH and T through which these cells modulate expression of their genes and gene products which are necessary for spermatogenesis within seminiferous tubule, during pubertal and adult phase of life [4]. We have recently shown that functional ability of infant Sc is inadequate as compared to pubertal Sc in rats [5] and sub-human primates [6]. Comparative evaluation of genes expressed by infant and pubertal Sc exposed to identical hormonal milieu may lead to identification of gene(s) or gene product(s) relevant to onset of robust spermatogenesis during normal puberty but not during infancy.
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