UC San Diego

Gonadotropin-releasing hormone (GnRH) is a primary and essential regulator of vertebrate reproduction. When GnRH neurons are compromised, GnRH expression is attenuated, producing the condition Idiopathic Hypogonadotropic Hypogonadism (IHH). IHH is characterized by infertility and/or delayed or absent puberty. When this condition is accompanied by anosmia, it is termed Kallmann syndrome. Although it is clearly a crucial factor in the reproduction of mammalian species, little is known about the genetic regulators of GnRH neuronal ontogeny. In the work presented herein, we elucidate developmental and genetic mechanisms that control the migration and maturation of GnRH neurons, and therefore illuminate the novel mechanisms responsible for IHH. Furthermore, we have identified new genes influencing the relationship between nasal development and GnRH neuron migration- further elucidating the etiology of Kallmann syndrome. The two genes that are explored in the work presented here are the closely related homeodomain transcription factors, sine oculis-related homeobox 3 (Six3) and Six6. First, we present data demonstrating that Six3 regulates GnRH neuron migration through actions external to the GnRH neuron. Six3 heterozygous mice displayed disrupted migration of GnRH neurons and severe olfactory impairment. Interestingly when the role of Six3 specifically within the GnRH neuron was investigated using a GnRH specific cre-recombinase, we found that Six3 acts within the neuron to upregulate GnRH neuron number. In addition, we investigated the actions of the closely related gene Six6. Six6 was found to be essential for survival of GnRH neurons and maintenance of fertility in a Six6 knock-out mouse. Six6 was found to play a similar role within the GnRH neuron in enabling fertility; however, within the GnRH neuron, Six6 acts to regulate GnRH expression. These investigations have enabled us to garner knowledge concerning the novel regulatory mechanisms of this fascinating hormone; and, has allowed us to shed light on the causes of infertility plaguing ~7% of all couples.