title: Redundant and differential roles of transcription factors Gli1 and Gli2 in the development of mouse fetal Leydig cells.
abstract: Appearance of mouse fetal Leydig cells requires activation of the Hedgehog pathway. Upon binding to the membrane-bound receptor patched, Hedgehog ligands induce intracellular responses via a combined effect of Gli transcription factors. Szczepny et al. (Biol Reprod 2009; 80:258-263) found that Gli1, one of the three Gli transcription factors, is present in the fetal testis and that its expression is suppressed by the Hedgehog inhibitor cyclopamine. In this study, we investigated the involvement of the Gli1 and Gli2 factors in mouse fetal Leydig cell differentiation. The Gli1 and Gli2 transcription factors showed an overlapping expression pattern in the testis interstitium at the time when fetal Leydig cells appear. Despite their similar expression, Gli1 and Gli2 patterns were differentially regulated. Initial Gli1 and Gli2 expression depends upon an active Hedgehog pathway; however, maintenance of only Gli1, but not Gli2, expression requires activation of the pathway. Inactivation of either the Gli1 or Gli2 gene did not affect fetal Leydig cell development and testis morphology, suggesting a functional redundancy. When the transcriptional activity of both GLI1 and GLI2 was suppressed by a selective inhibitor, GANT61, in cultured fetal testes before the appearance of fetal Leydig cells, Gli1 and Gli2 expression and steroidogenic marker activity were completely abolished. However at later stages when Leydig cells were already present, GANT61 treatment inhibited Gli1 expression but had no effects on Gli2 expression and fetal Leydig cell appearance. Our results reveal overlapping and redundant Gli1 and Gli2 roles in fetal Leydig cell differentiation and a novel regulation of Gli2 expression in the fetal testis.
authors.affiliation: Department of Cell and Developmental Biology, University of Illinois, Urbana, IL, USA.
authors.forename: Ivraym
authors.initials: I
authors.lastname: Barsoum
authors.forename: Humphrey H C
authors.initials: HH
authors.lastname: Yao
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002786:Cholesterol Side-Chain Cleavage Enzyme / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000187:drug effects / Q000378:metabolism; D017930:Genes, Reporter; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors; D017403:In Situ Hybridization; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007985:Leydig Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009924:Organ Culture Techniques; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids / Q000494:pharmacology; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
chemical_list: C551027:GANT 61; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D011725:Pyridines; D011743:Pyrimidines; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2; D002786:Cholesterol Side-Chain Cleavage Enzyme; C000541:cyclopamine