A small population of hypothalamic neurons govern fertility: the critical role of VAX1 in GnRH neuron development and fertility maintenance.
Fertility depends on the correct maturation and function of approximately 800 gonadotropin-releasing hormone (GnRH) neurons in the brain. GnRH neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates fertility. In adulthood, GnRH neurons are scattered throughout the anterior hypothalamic area and project to the median eminence, where GnRH is released into the portal vasculature to stimulate release of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary. LH and FSH then regulate gonadal steroidogenesis and gametogenesis. Absence of GnRH neurons or inappropriate GnRH release leads to infertility. Despite the critical role of GnRH neurons in fertility, we still have a limited understanding of the genes responsible for proper GnRH neuron development and function in adulthood. GnRH neurons originate in the olfactory placode then migrate into the brain. Homeodomain transcription factors expressed within GnRH neurons or along their migratory path are candidate genes for inherited infertility. Using a combinedin vitroandin vivoapproach, we have identified Ventral Anterior Homeobox 1 (Vax1) as a novel homeodomain transcription factor responsible for GnRH neuron maturation and fertility. GnRH neuron counts inVax1knock-out embryos revealedVax1to be required for the presence of GnRH-expressing cells at embryonic day 17.5 (E17.5), but not at E13.5. To localize the effects ofVax1on fertility, we generatedVax1floxmice and crossed them withGnrhcremice to specifically deleteVax1within GnRH neurons. GnRH staining inVax1flox/flox:GnRHcremice show a total absence of GnRH expression in the adult. We performed lineage tracing inVax1flox/flox:GnRHcre:RosaLacZmice which proved GnRH neurons to be alive, but incapable of expressing GnRH. The absence of GnRH leads to delayed puberty, hypogonadism and complete infertility in both sexes. Finally, using the immortalized model GnRH neuron cell lines, GN11 and GT1-7, we show that VAX1 is a direct regulator ofGnrh1transcription by binding key ATTA sites within theGnrh1promoter. This study identifies VAX1 as a key transcription factor regulating GnRH expression and establishes VAX1 as a novel candidate gene implicated in heritable infertility.
Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Hanne M
HM
Hoffmann
Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, La Jolla, CA 92037, USA.
Pamela L
PL
Mellon
GnRH neuron; Inherited infertility; VAX1; development; homeodomain transcription factor; hypogonadism