INSL3/RXFP2 Signaling in Testicular Descent

Abstract

Mutations of the insulin-like 3 (INSL3) hormone or its receptor RXFP2 cause intraabdominal cryptorchidism in male mice. Specific RXFP2 expression in mouse gubernacula was detected at embryonic day 14.5 (E14.5) and markedly increased after birth in the developing cremaster muscle, as well as in the epididymis, testicular Leydig and germ cells. INSL3 treatment stimulated cell proliferation of embryonic gubernacular and Leydig cells implicating active INSL3-mediated signaling. The transcription factor SOX9, a known male sex determination factor, up-regulated the activity of the RXFP2 promoter. INSL3 is sufficient to direct the first transabdominal phase of testicular descent in the absence of hypothalamic-pituitary-gonadal axis signaling or Hoxa10 but their presence is important for inguinoscrotal testicular descent. Similarly, conditional ablation of the androgen receptor gene in gubernacular cells resulted in disruption of inguinoscrotal descent. We performed mutation screening of INSL3 and RXFP2 in human patients with cryptorchidism and control subjects from different populations in Europe and USA. Several missense mutations were described in both the INSL3 and RXFP2 genes. A novel V39G INSL3 mutation in a patient with cryptorchidism was identified, however the functional analysis of the mutant peptide did not reveal compromised function. In more than 2000 patients and controls analyzed to date the T222P RXFP2 mutation is the only one strongly associated with the mutant phenotype. The T222P mutant receptor transfected into 293T cells had severely decreased cell membrane expression, providing the basis for the functional deficiency of this mutation.

Functional link between bone morphogenetic proteins and insulin-like peptide 3 signaling in modulating ovarian androgen production

“…male reproductive system, being involved in the first (transabdominal) phase of testicular descent (19). Although it has been known for some time that INSL3 is also expressed in the adult ovary, primarily in TCs (20) and luteal tissue (21,22), its potential physiological role in the regulation of ovarian function and steroidogenesis is poorly defined.…”

Development of the Gubernaculum During Testicular Descent in the Rat

“…It is generally agreed that testicular descent in mammals occurs in two distinct steps with different anatomy and hormonal regulation (Hutson, 1985;Amann and Veeramachaneni, 2007;Foresta et al, 2008;Hughes and Acerini, 2008;Feng et al, 2009). In the first, or transabdominal phase, the genitoinguinal ligament, also known as the ''gubernaculum,'' undergoes enlargement or the ''swelling reaction.''…”

Testicular descent, sperm maturation and capacitation. Lessons from our most distant relatives, the monotremes

“…Consequently, a knowledge of the processes involved in and the origins and biological significance of testicular descent may be most informative for understanding the condition. In this respect, it is established that, in mice and humans, INSL3 (insulin-like factor 3) acts through the receptor LGR8 (RXFP2, GREAT) to mediate testicular descent via its effect on growth of the gubernaculum's primordia and caudal genitoringuinal ligament, and mutation of the genes for either of these proteins is associated with failure of testicular descent in developing males (Nef and Parada 1999;Zimmermann et al 1999;Bogatcheva et al 2003;Kamat et al 2004;Wilhelm and Koopman 2006;Feng et al 2009;Ferlin et al 2009). …”