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- Title
Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility.
- Authors
Hoffmann, Hanne M.; Trang, Crystal; Gong, Ping; Kimura, Ikuo; Pandolfi, Erica C.; Mellon, Pamela L.
- Abstract
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 that Vax1 deletion from GnRH neurons leads to complete infertility in males and females. Specifically, global Vax1 knock-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 in Vax1,flox/flox:GnRHlcre:RosalacZ mice. This identified VAX1 as essential for maintaining expression of Gnrhl. The absence of GnRH staining in adult Vax1,flox/flox:GnRHlcre mice led to delayed puberty, hypogonadism, and infertility. To address the mechanism by which VAX1 maintains Gnrhl transcription, the capacity of VAX1 to regulate Gnrhl transcription 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 (El) 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.
- Subjects
GONADOTROPIN releasing hormone; HYPOGONADISM; INFERTILITY; HOMEOBOX genes; GENE expression
- Publication
Journal of Neuroscience, 2016, Vol 36, Issue 12, p3506
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.2723-15.2016