<i>Prokr2-</i>Deficient Mice Display Vascular Dysmorphology of the Fetal Testes: Potential Implications for Kallmann Syndrome Aetiology

Abstract

Kallmann syndrome is a form of hypogonadotropic hypogonadism also associated with the loss of smell. It is a phenotypically and genetically heterogeneous disorder, with mutations in several known causative genes now accounting for approximately 30% of cases. The prevalence for the disease is also much higher in males than in females, a phenomenon that remains to be fully explained. Here, we show that loss of Prokr2, which is linked to autosomal recessive Kallmann syndrome type 3 (KAL3; OMIM 244200), affects fetal testis differentiation in mice. We find that Prokr2 is specifically expressed in the XY gonads during sex determination and fetal sexual differentiation, and knockout mice display a variable degree of compromised vasculature in the fetal testes. This phenotype offers potential insight into the clinical heterogeneity observed within familial cases, and may contribute to the gender bias in Kallmann syndrome patients.

Purification and Transcriptomic Analysis of Mouse Fetal Leydig Cells Reveals Candidate Genes for Specification of Gonadal Steroidogenic Cells1

“…By checking previously published 11.5 dpc microarray data for genes we identified as FLC-upregulated at 12.5 dpc, we identified 10 robustly-expressed putative pre-steroidogenic FLC marker genes. One of these is Prokr2 which we have previously shown to be expressed in the XY 11.5 dpc genital ridge [46] thereby validating this approach. Some of these 10 genes may prove useful in identifying pre-FLCs before they begin to express characteristic steroidogenic enzyme genes.…”

“…Mutations in PROKR2 (OMIM: 244200; [64]) and TACR3 (OMIM: 614840; [65,66]) are associated with hypogonadotrophic hypogonadism in humans and mice. As many of the factors associated with neuroactive-ligand receptor activation and other neuronal processes are expressed robustly in the FLCs or the Sertoli cells of the developing testis (this study; [21]) it is tempting to speculate that gonadal production of these factors may precede HPG-driven production and explain male bias in individuals affected by hypogonadotrophic hypogonadism [46,55,64,67].…”

“…Prokr2-/-mice have reproductive defects and we have previously shown that there was no change in expression of FLC marker HSD3β/Hsd3β in Prokr2 -/-embryos compared to wild-type littermates [41,46]. However, embryonic Prokr2 -/-testes display vasculature dysmorphology, a phenotype often associated with FLC impairment [10,46].…”

“…Determining which cell types a given gene is expressed in has hitherto been typically a labour intensive task [46,47]. Aside from providing the basis for our transcriptomic analysis, the system we developed will be useful in future studies designed to assign expression of any novel gene to a particular cell lineage using qRT-PCR.…”

“…However, embryonic Prokr2 -/-testes display vasculature dysmorphology, a phenotype often associated with FLC impairment [10,46]. Tacr3-/-mice have a variety of reproductive and fertility defects and a postnatal hormone profile similar to several other GnRHdeficient mouse models [41,42,68].…”