Fig. 1

Normal male phenotypic sex development highlighting the role of DHH. Testis determination requires SRY and one DAX1 copy, whilst with two DAX1 copies and a lack of SRY an ovary is determined. In the bipotential gonad, SF1, WT1 and GATA4 upregulate SRY which in turn upregulates SOX9; SOX9 is pivotal to testis determination. Upregulation of SRY and SOX9 overcomes the action of genes promoting female sex development including DAX1 and β-catenin. With upregulation of SOX9, multiple feed-forward loops then accelerate male pathway commitment. Other genes, including DHH, as well as growth factors also have roles in promoting testis determination. Following testis determination, Sertoli cells secrete AMH leading to Müllerian duct regression; Müllerian ducts would otherwise form the fallopian tubes, uterus, cervix and upper vagina. Sertoli cells also secrete DHH which is important for Leydig cell development and Sertoli-peritubular cell interaction. Responding to luteinizing hormone (via LHCGR), a functional Leydig cell produces testosterone via steroidogenesis, requiring SF1 and steroidogenesis enzymes. Converted to DHT via 5α-reductase, testosterone and DHT induce Wolffian duct differentiation (leading to vas deferens, seminal vesicle and prostate formation) and external genitalia masculinization through actions on the androgen receptor. In the absence of functional Leydig cells female external genitalia form and testes fail to descend. Blue block arrows indicate DHH’s involvement in male sex development. Lines ending in an arrow denote a positive/up-regulating effect whilst lines ending in a perpendicular bar indicate a negative/down-regulating effect. Abbreviations: AMH– Anti-Müllerian hormone, ATRX– X-linked alpha thalassemia and mental retardation, DAX1– dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1, DHH– desert hedgehog, DHT– dihydrotestosterone, FGF9– fibroblast growth factor 9, INSL3– insulin-like protein 3, LHCGR– Luteinizing hormone common G-protein receptor, NGFs– nerve growth factors, PDGFs– platelet derived growth factors, PGD2– prostaglandin D2, RSPO1– R-spondin-1, SF1– steroidogenic factor-1, SRY– sex determining region on the Y chromosome, WT1– Wilms’ tumour suppressor gene 1