title: The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice.
abstract: The small heterodimer partner (SHP) is an atypical nuclear receptor known mainly for its role in bile acid homeostasis in the enterohepatic tract. We explore here the role of SHP in the testis. SHP is expressed in the interstitial compartment of the adult testes, which contain the Leydig cells. SHP there inhibits the expression of steroidogenic genes, on the one hand by inhibiting the expression of the nuclear receptors steroidogenic factor-1 and liver receptor homolog-1 (lrh-1), and on the other hand by directly repressing the transcriptional activity of LRH-1. Consequently, in SHP knockout mice, testicular testosterone synthesis is increased independently of the hypothalamus-pituitary axis. Independent of its action on androgen synthesis, SHP also determines the timing of germ cell differentiation by controlling testicular retinoic acid metabolism. Through the inhibition of the transcriptional activity of retinoic acid receptors, SHP controls the expression of stimulated by retinoic acid gene 8 (stra8) - a gene that is indispensable for germ cell meiosis and differentiation. Together, our data demonstrate new roles for SHP in testicular androgen and retinoic acid metabolism, making SHP a testicular gatekeeper of the timing of male sexual maturation.
authors.affiliation: Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Centre National de la Recherche Scientifique (CNRS)/Institut National de la Santé et de la Recherche Médicale (INSERM)/Université Louis Pasteur (ULP), 67404 Illkirch, France.
authors.forename: David H
authors.initials: DH
authors.lastname: Volle
authors.forename: Rajesha
authors.initials: R
authors.lastname: Duggavathi
authors.forename: Benjamin C
authors.initials: BC
authors.lastname: Magnier
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: Jean-Marc A
authors.initials: JM
authors.lastname: Lobaccaro
authors.forename: Guido
authors.initials: G
authors.lastname: Verhoeven
authors.forename: Kristina
authors.initials: K
authors.lastname: Schoonjans
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D005854:Germ Cells / Q000166:cytology; D012739:Gonadal Steroid Hormones / Q000096:biosynthesis; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012741:Sexual Maturation; D015398:Signal Transduction; D054339:Steroidogenic Factor 1; D013737:Testis / Q000378:metabolism / Q000502:physiology*; D013739:Testosterone / Q000097:blood; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000502:physiology; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004268:DNA-Binding Proteins; D012739:Gonadal Steroid Hormones; D018160:Receptors, Cytoplasmic and Nuclear; D054339:Steroidogenic Factor 1; D013739:Testosterone; D014157:Transcription Factors; D014212:Tretinoin; D000099150:Receptor, Farnesoid X-Activated; C431936:Nr5a2 protein, mouse; C099713:nuclear receptor subfamily 0, group B, member 2; C515058:steroidogenic factor 1, mouse