Deletion of Vax1 from Gonadotropin-Releasing Hormone (GnRH) Neurons Abolishes GnRH Expression and Leads to Hypogonadism and Infertility

Overview

Journal J Neurosci

Specialty Neurology

Date 2016 Mar 26

PMID 27013679

Citations 24

Authors

Hanne M Hoffmann

Crystal Trang

Ping Gong

Ikuo Kimura

Erica C Pandolfi

Pamela L Mellon

Affiliations

Soon will be listed here.

Abstract

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 of Gnrh1 gene expression and deletion of Vax1 from GnRH neurons leads to complete infertility.

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References

Valdes-Socin H, Rubio Almanza M, Tome Fernandez-Ladreda M, Debray F, Bours V, Beckers A . Reproduction, smell, and neurodevelopmental disorders: genetic defects in different hypogonadotropic hypogonadal syndromes. Front Endocrinol (Lausanne). 2014; 5:109. PMC: 4088923. DOI: 10.3389/fendo.2014.00109. View

Soriano P . Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat Genet. 1999; 21(1):70-1. DOI: 10.1038/5007. View

Bertuzzi S, Hindges R, Mui S, OLeary D, Lemke G . The homeodomain protein vax1 is required for axon guidance and major tract formation in the developing forebrain. Genes Dev. 1999; 13(23):3092-105. PMC: 317177. DOI: 10.1101/gad.13.23.3092. View

Hoffmann H, Tamrazian A, Xie H, Perez-Millan M, Kauffman A, Mellon P . Heterozygous deletion of ventral anterior homeobox (vax1) causes subfertility in mice. Endocrinology. 2014; 155(10):4043-53. PMC: 4164932. DOI: 10.1210/en.2014-1277. View

Yoon H, Enquist L, Dulac C . Olfactory inputs to hypothalamic neurons controlling reproduction and fertility. Cell. 2005; 123(4):669-82. DOI: 10.1016/j.cell.2005.08.039. View

Diaczok D, Divall S, Matsuo I, Wondisford F, Wolfe A, Radovick S . Deletion of Otx2 in GnRH neurons results in a mouse model of hypogonadotropic hypogonadism. Mol Endocrinol. 2011; 25(5):833-46. PMC: 3082331. DOI: 10.1210/me.2010-0271. View

Kauffman A . Coming of age in the kisspeptin era: sex differences, development, and puberty. Mol Cell Endocrinol. 2010; 324(1-2):51-63. PMC: 2902563. DOI: 10.1016/j.mce.2010.01.017. View

Lawson M, MacConell L, Kim J, Powl B, Nelson S, Mellon P . Neuron-specific expression in vivo by defined transcription regulatory elements of the GnRH gene. Endocrinology. 2002; 143(4):1404-12. DOI: 10.1210/endo.143.4.8751. View

Kim J, Tolson K, Dhamija S, Kauffman A . Developmental GnRH signaling is not required for sexual differentiation of kisspeptin neurons but is needed for maximal Kiss1 gene expression in adult females. Endocrinology. 2013; 154(9):3273-83. PMC: 3749477. DOI: 10.1210/en.2013-1271. View

10.

Tsai P, Gill J . Mechanisms of disease: Insights into X-linked and autosomal-dominant Kallmann syndrome. Nat Clin Pract Endocrinol Metab. 2006; 2(3):160-71. DOI: 10.1038/ncpendmet0119. View

11.

Wolfe A, Divall S, Singh S, Nikrodhanond A, Baria A, Le W . Temporal and spatial regulation of CRE recombinase expression in gonadotrophin-releasing hormone neurones in the mouse. J Neuroendocrinol. 2008; 20(7):909-16. PMC: 2658716. DOI: 10.1111/j.1365-2826.2008.01746.x. View

12.

Pitteloud N, Quinton R, Pearce S, Raivio T, Acierno J, Dwyer A . Digenic mutations account for variable phenotypes in idiopathic hypogonadotropic hypogonadism. J Clin Invest. 2007; 117(2):457-63. PMC: 1765517. DOI: 10.1172/JCI29884. View

13.

Gill J, Wadas B, Chen P, Portillo W, Reyna A, Jorgensen E . The gonadotropin-releasing hormone (GnRH) neuronal population is normal in size and distribution in GnRH-deficient and GnRH receptor-mutant hypogonadal mice. Endocrinology. 2008; 149(9):4596-604. PMC: 2553368. DOI: 10.1210/en.2008-0403. View

14.

Hallonet M, Hollemann T, Pieler T, Gruss P . Vax1, a novel homeobox-containing gene, directs development of the basal forebrain and visual system. Genes Dev. 1999; 13(23):3106-14. PMC: 317183. DOI: 10.1101/gad.13.23.3106. View

15.

Kim N, Min K, Kang K, Lee E, Kim H, Moon K . Regulation of retinal axon growth by secreted Vax1 homeodomain protein. Elife. 2014; 3:e02671. PMC: 4178304. DOI: 10.7554/eLife.02671. View

16.

Gibson M, Kasowski H, Dobrjansky A . Continuous gonadotropin-releasing hormone infusion stimulates dramatic gonadal development in hypogonadal female mice. Biol Reprod. 1994; 50(3):680-5. DOI: 10.1095/biolreprod50.3.680. View

17.

Livak K, Schmittgen T . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods. 2002; 25(4):402-8. DOI: 10.1006/meth.2001.1262. View

18.

Lapatto R, Pallais J, Zhang D, Chan Y, Mahan A, Cerrato F . Kiss1-/- mice exhibit more variable hypogonadism than Gpr54-/- mice. Endocrinology. 2007; 148(10):4927-36. DOI: 10.1210/en.2007-0078. View

19.

Clarkson J, dAnglemont de Tassigny X, Moreno A, Colledge W, Herbison A . Kisspeptin-GPR54 signaling is essential for preovulatory gonadotropin-releasing hormone neuron activation and the luteinizing hormone surge. J Neurosci. 2008; 28(35):8691-7. PMC: 6670827. DOI: 10.1523/JNEUROSCI.1775-08.2008. View

20.

Boden M, Kennaway D . Circadian rhythms and reproduction. Reproduction. 2006; 132(3):379-92. DOI: 10.1530/rep.1.00614. View