Hedgehog signalling promotes germ cell survival in the rat testis

Abstract

Hedgehog (Hh) signalling has a crucial role in testis development. Sertoli cell-derived desert hedgehog (DHH) guides the formation of testis cords and differentiation of foetal-type Leydig cells. Dhh mutant mice are infertile due to a block in germ cell differentiation, hypogonadism and hypoandrogenism. Hh signalling pathway components are also expressed in postnatal testis. In the rat testis the transcription factor of the Hh pathway, glioma-associated oncogene homologue (GLI1), is expressed by a wide variety of germ cells. This suggests that Hh signalling is involved in spermatogenesis at many different levels. Our data show that canonical Hh signalling is turned off in early condensing spermatids that strongly express the negative regulator of the pathway, suppressor of fused (SUFU). Most of the Hh pathway specific mRNAs display the highest values in stages II–VI of the rat seminiferous epithelial cycle. The key endocrine regulator of germ cell differentiation, FSH, down-regulates Dhh mRNA levels in vitro. Hh signalling inhibition in vitro leads to massive apoptosis of germ cells. In prepubertal rat testis imatinib mesylate-induced inhibition of tyrosine kinases impinges on Dhh transcript levels and Hh signalling. Our data indicate that Hh signalling is part of the paracrine signalling network in the rat testis. It promotes the survival of germ cells and is suppressed by FSH.

Dynamic Hedgehog signalling pathway activity in germline stem cells

“…The present study reinforces previous evidence that Hh signalling pathway is modulated by transcriptional regulation of the mRNAs encoding pathway receptors, ligands and intracellular signalling modulators (Farzan et al 2009), including during progressive differentiation of male germ cells (Makela et al 2011, Morales et al 2009, Szczepny et al 2006). Both spermatogonia and spermatocytes in the adult rat testis contain Ptc2, Gli1 and Gli2 mRNAs, supporting other data which identify mitotic and meiotic male germ cells as active in Hh signalling (Kroft et al 2001, Szczepny et al 2009).…”

“…Localization of glioma-associated oncogene homologue (Gli) transcription factor-1 (Gli1) in spermatogonia, spermatocytes and spermatids indicates these cells have active Hh signalling (Kroft et al 2001, Makela et al 2011), due to the fact that Gli1 is a direct target of pathway activity (Scales and de Sauvage 2009). Transcripts and/or proteins encoding the transmembrane receptors Patched (Ptc)-1, Ptc2 and Smoothened (Smo), and the positive pathway regulator, Fused (Fu), are present in both mitotic and meiotic murine germ cells (Morales et al 2009, Szczepny et al 2006), demonstrating these cells have the machinery required for Hh ligand responsiveness.…”

“…The observation that ectopic Gli1 synthesis in spermatocytes caused meiotic arrest (Kroft et al 2001) provides additional evidence that Hh pathway activity must be regulated for normal fertility. More recently, short term culture experiments with Hh signalling inhibitors have demonstrated that Hh pathway activity affects mitotic and meiotic germ cells as well as Sertoli cells (Makela et al 2011, Szczepny et al 2009). …”

Inhibition of Hedgehog signaling in the gastrointestinal tract: Targeting the cancer microenvironment

“…In the gastrointestinal tract, the major ligands expressed are Shh in the proximal gut (esophagus, stomach, liver and pancreas) and Ihh in the midgut and hindgut (small intestine and colon) 20 . However, Dhh expression appears to be tissue-restricted to the nervous system and testes 21 . Some tissues exhibit differential potency amongst the ligand paralogs with respect to Hh signaling (Shh>>>Ihh>Dhh).…”

Role of the Hedgehog Signaling Pathway in Regulating the Behavior of Germline Stem Cells

“…Meanwhile, SuFu is a negative regulatory factor in the Hh pathway, and it cannot be detected in earlier differentiation periods of SSCs. However, when SSCs develop into mature spermatids, the expression of SuFu constantly increases and inhibits Gli transcriptional activity, which results in the suppression of Dhh signaling in advanced circular sperm cells [ 38 – 40 ]. Therefore, as SSCs differentiate, their Hh signaling activity continuously decreases.…”