National Ataxia Foundation Young Investigator Research Grant, the Cleon C. Arrington
Research Ini...(RIG-93)
Hungarian Brain Research Program(2017-1.2.1-NKP-2017-00002)
National Science Foundation of Hungary(K128317)
NIGMS(R01GM115763)
NINDS(R21NS116760)
NIDA(R01DA041529)
Recessive mutations in RNF216/TRIAD3 cause Gordon Holmes syndrome (GHS), in which
dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis and neuro-degeneration
are thought to be core phenotypes. We knocked out Rnf216/Triad3 in a gonadotropin-releasing
hormone (GnRH) hypothalamic cell line. Rnf216/Triad3 knockout (KO) cells had decreased
steady-state GnRH and calcium transients. Rnf216/Triad3 KO adult mice had reductions
in GnRH neuron soma size and GnRH production without changes in neuron densities.
In addition, KO male mice had smaller testicular volumes that were accompanied by
an abnormal release of inhibin B and follicle-stimulating hormone, whereas KO females
exhibited irregular estrous cycling. KO males, but not females, had reactive microglia
in the hypothalamus. Conditional deletion of Rnf216/Triad3 in neural stem cells caused
abnormal microglia expression in males, but reproductive function remained unaffected.
Our findings show that dysfunction of RNF216/TRIAD3 affects the HPG axis and microglia
in a region- and sex-dependent manner, implicating sex-specific therapeutic interventions
for GHS.
