title: Sertoli cell androgen receptor expression regulates temporal fetal and adult Leydig cell differentiation, function, and population size.
abstract: We recently created a mouse model displaying precocious Sertoli cell (SC) and spermatogenic development induced by SC-specific transgenic androgen receptor expression (TgSCAR). Here we reveal that TgSCAR regulates the development, function, and absolute number of Leydig cells (LCs). Total fetal and adult type LC numbers were reduced in postnatal and adult TgSCAR vs control testes, despite normal circulating LH levels. Normal LC to SC ratios found in TgSCAR testes indicate that SC androgen receptor (SCAR)-mediated activity confers a quorum-dependent relationship between total SC and LC numbers. TgSCAR enhanced LC differentiation, shown by elevated ratios of advanced to immature LC types, and reduced LC proliferation in postnatal TgSCAR vs control testes. Postnatal TgSCAR testes displayed up-regulated expression of coupled ligand-receptor transcripts (Amh-Amhr2, Dhh-Ptch1, Pdgfa-Pdgfra) for potential SCAR-stimulated paracrine pathways, which may coordinate LC differentiation. Neonatal TgSCAR testes displayed normal T and dihydrotestosterone levels despite differential changes to steroidogenic gene expression, with down-regulated Star, Cyp11a1, and Cyp17a1 expression contrasting with up-regulated Hsd3b1, Hsd17b3, and Srd5a1 expression. TgSCAR males also displayed elevated postnatal and normal adult serum testosterone levels, despite reduced LC numbers. Enhanced adult-type LC steroidogenic output was revealed by increased pubertal testicular T, dihydrotestosterone, 3α-diol and 3β-diol levels per LC and up-regulated steroidogenic gene (Nr5a1, Lhr, Cyp11a1, Cyp17a1, Hsd3b6, Srd5a1) expression in pubertal or adult TgSCAR vs control males, suggesting regulatory mechanisms maintain androgen levels independently of absolute LC numbers. Our unique gain-of-function TgSCAR model has revealed that SCAR activity controls temporal LC differentiation, steroidogenic function, and population size.
authors.affiliation: ANZAC Research Institute, Concord Hospital, Sydney, New South Wales 2139, Australia.
authors.forename: Rasmani
authors.initials: R
authors.lastname: Hazra
authors.forename: Mark
authors.initials: M
authors.lastname: Jimenez
authors.forename: Reena
authors.initials: R
authors.lastname: Desai
authors.forename: David J
authors.initials: DJ
authors.lastname: Handelsman
authors.forename: Charles M
authors.initials: CM
authors.lastname: Allan
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D057898:Hemizygote; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007985:Leydig Cells / Q000166:cytology* / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012708:Sertoli Cells / Q000166:cytology / Q000378:metabolism*; D046468:Sexual Development; D013737:Testis / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D045165:Testosterone Congeners / Q000097:blood / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C410798:AR protein, human; D015415:Biomarkers; D007527:Isoenzymes; D008024:Ligands; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011944:Receptors, Androgen; D011956:Receptors, Cell Surface; D018000:Receptors, Peptide; D018125:Receptors, Transforming Growth Factor beta; D045165:Testosterone Congeners; C084621:anti-Mullerian hormone receptor; D020796:Receptor, Platelet-Derived Growth Factor alpha