The small heterodimer partner is a gonadal gatekeeper of sexual maturation in male mice

Genes Dev. 2007 Feb 1;21(3):303-15. doi: 10.1101/gad.409307.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation
  • Cell Proliferation
  • DNA-Binding Proteins / metabolism
  • Germ Cells / cytology
  • Gonadal Steroid Hormones / biosynthesis
  • Leydig Cells / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Biological
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / metabolism
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Sexual Maturation*
  • Signal Transduction
  • Steroidogenic Factor 1
  • Testis / metabolism
  • Testis / physiology*
  • Testosterone / blood
  • Transcription Factors / metabolism
  • Tretinoin / physiology


  • DNA-Binding Proteins
  • Gonadal Steroid Hormones
  • Nr5a2 protein, mouse
  • Receptors, Cytoplasmic and Nuclear
  • Steroidogenic Factor 1
  • Transcription Factors
  • nuclear receptor subfamily 0, group B, member 2
  • steroidogenic factor 1, mouse
  • farnesoid X-activated receptor
  • Testosterone
  • Tretinoin