THE HOMEODOMAIN PROTEINS SIX3 AND SIX6 ARE IMPORTANT IN THE DEVELOPMENT OF GNRH NEURONS IN MICE
Erica Pandolfi, Pamela Mellon.
University of California, San Diego, La Jolla, CA.
A reduction in gonadotropin-releasing hormone (GnRH) neurons causes GnRH deficiency and infertility. GnRH neurons originate in the olfactory placode and migrate to the hypothalamus. Two genes that play a role in the development of these neurons are Six3 and Six6. However, the effect of Six3 on neuronal development has not yet been tested, and further exploration into the loss of GnRH neurons in the Six6KO mouse model must be conducted. The purpose of our work is to determine what role Six3 and Six6 play in the development of GnRH neurons and fertility. We hypothesize that Six3 and Six6 are essential regulators of GnRH neuronal development, and are important in the development of GnRH neurons. Mice with a specific deletion of Six3 from GnRH neurons were used, as well as Six6KO mice. Neuronal counting in Six3Flox/GnRHCre mice showed a 30% increase in GnRH neuron numbers in the embryo and adult. This 30% increase in GnRH neurons did not significantly impact fertility. In contrast, neuronal counting revealed that Six6KO mice first showed reduction in the number of GnRH neurons at E14.5. The balance of Six3 and Six6 in GnRH neurons is crucial for the correct maturation of GnRH neurons, and determines the number of GnRH neurons in the mouse, thus regulating fertility. Our findings support the hypothesis that the Six6 protein is an essential positive regulator of GnRH neuron survival; and that the Six3 protein functions as an inhibitor of GnRH neuron proliferation or survival.