| First Author | Hoffmann HM | Year | 2016 |
| Journal | J Neurosci | Volume | 36 |
| Issue | 12 | Pages | 3506-18 |
| PubMed ID | 27013679 | Mgi Jnum | J:231756 |
| Mgi Id | MGI:5774894 | Doi | 10.1523/JNEUROSCI.2723-15.2016 |
| Citation | Hoffmann HM, et al. (2016) Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility. J Neurosci 36(12):3506-18 |
| abstractText | Hypothalamic gonadotropin-releasing hormone (GnRH) neurons are at the apex of the hypothalamic-pituitary-gonadal axis that regulates mammalian fertility. Herein we demonstrate a critical role for the homeodomain transcription factor ventral anterior homeobox 1 (VAX1) in GnRH neuron maturation and show thatVax1deletion from GnRH neurons leads to complete infertility in males and females. Specifically, globalVax1knock-out embryos had normal numbers of GnRH neurons at 13 d of gestation, but no GnRH staining was detected by embryonic day 17. To identify the role of VAX1 specifically in GnRH neuron development,Vax1(flox)mice were generated and lineage tracing performed inVax1(flox/flox):GnRH(cre):RosaLacZmice. This identified VAX1 as essential for maintaining expression ofGnrh1 The absence of GnRH staining in adultVax1(flox/flox):GnRH(cre)mice led to delayed puberty, hypogonadism, and infertility. To address the mechanism by which VAX1 maintainsGnrh1transcription, the capacity of VAX1 to regulateGnrh1transcription was evaluated in the GnRH cell lines GN11 and GT1-7. As determined by luciferase and electrophoretic mobility shift assays, we found VAX1 to be a direct activator of the GnRH promoter through binding to four ATTA sites in the GnRH enhancer (E1) and proximal promoter (P), and able to compete with the homeoprotein SIX6 for occupation of the identified ATTA sites in the GnRH promoter. We conclude that VAX1 is expressed in GnRH neurons where it is required for GnRH neuron expression of GnRH and maintenance of fertility in mice. SIGNIFICANCE STATEMENT: Infertility classified as idiopathic hypogonadotropic hypogonadism (IHH) is characterized by delayed or absent sexual maturation and low sex steroid levels due to alterations in neuroendocrine control of the hypothalamic-pituitary-gonadal axis. The incidence of IHH is 1-10 cases per 100,000 births. Although extensive efforts have been invested in identifying genes giving rise to IHH, >50% of cases have unknown genetic origins. We recently showed that haploinsufficiency of ventral anterior homeobox 1 (Vax1) leads to subfertility, making it a candidate in polygenic IHH. In this study, we investigate the mechanism by which VAX1 controls fertility finding that VAX1 is required for maintenance ofGnrh1gene expression and deletion ofVax1from GnRH neurons leads to complete infertility. |
