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Hypothalamic GnRH (luteinizing hormone-releasing hormone) neurons are crucial for the hypothalamic-pituitary-gonadal (HPG) axis, which regulates mammalian fertility. Insufficient GnRH disrupts the HPG axis and is often associated with the genetic condition idiopathic hypogonadotropic hypogonadism (IHH). The homeodomain protein sine oculis-related homeobox 6 (Six6) is required for the development of GnRH neurons. Although it is known that Six6 is specifically expressed within a more mature GnRH neuronal cell line and that overexpression of Six6 induces GnRH transcription in these cells, the direct role of Six6 within the GnRH neuron in vivo is unknown. Here we find that global Six6 knockout (KO) embryos show apoptosis of GnRH neurons beginning at embryonic day 14.5 with 90% loss of GnRH neurons by postnatal day 1. We sought to determine whether the hypogonadism and infertility reported in the Six6KO mice are generated via actions within the GnRH neuron in vivo by creating a Six6-flox mouse and crossing it with the LHRHcre mouse. Loss of Six6 specifically within the GnRH neuron abolished GnRH expression in ∼0% of GnRH neurons. We further demonstrated that deletion of Six6 only within the GnRH neuron leads to infertility, hypogonadism, hypogonadotropism, and delayed puberty. We conclude that Six6 plays distinct roles in maintaining fertility in the GnRH neuron vs in the migratory environment of the GnRH neuron by maintaining expression of GnRH and survival of GnRH neurons, respectively. These results increase knowledge of the role of Six6 in the brain and may offer insight into the mechanism of IHH.
Pubmed ID: 31211355
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This polyclonal targets RFP
View all literature mentionsThis unknown targets GnRH1
View all literature mentionsThis polyclonal targets Luteinizing Hormone Releasing Hormone
View all literature mentionsThis polyclonal targets beta Galactosidase
View all literature mentionsMus musculus with name B6;129S4-Gt(ROSA)26Sortm1Sor/J from IMSR.
View all literature mentionsAllele Detail: Transgenic This is a legacy resource.
View all literature mentionsAllele Detail: Targeted This is a legacy resource.
View all literature mentionsAllele Detail: Transgenic This is a legacy resource.
View all literature mentionsMus musculus with name B6.Cg-Tg(ACTFLPe)9205Dym/J from IMSR.
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