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Open Access Publications from the University of California

The effect of homeodomain genes Six3 and Six6 on GnRH neuronal migration and apoptosis

  • Author(s): Sitts, Lauren Diane
  • Advisor(s): Mellon, Pamela L
  • Spitzer, Nicholas C
  • et al.

Infertility affects between 8-12% of couples worldwide and treatment can be very costly. One cause of infertility is Idiopathic Hypogonadotropic Hypogonadism (IHH), which can arise from the loss of gonadotropin-releasing hormone (GnRH). Many of the genes associated with IHH are currently unknown. Six3 and Six6 are genes associated with infertility in mouse models. Disruption of either Six3 or Six6 causes a decrease in the number of GnRH neurons found in the hypothalamus. The Six3 heterozygous mouse loses GnRH neurons to mismigration, whereas the Six6 knockout mouse loses GnRH neurons to apoptosis. To provide further insight into the mechanisms for the loss of GnRH neurons, we studied cell migration and apoptosis factors present along the migratory pathway of GnRH neurons. Our hypothesis was that, without adequate levels of these factors, GnRH neurons may die, become lost, or halt migration. We found that haploinsufficiency of Six3 leads to a trend towards a reduction in Npn2 and Nelf mRNA expression within the hypothalamus, and both of these factors have been shown to have a significant effect on the guidance of GnRH neurons. We found that complete loss of Six6 leads to a trend toward reduction in apoptotic factor Dach1, which is a potential novel regulator of GnRH neurons. Overall our findings support the idea that Six3 and Six6 affect the migratory environment that supports GnRH neuron migration from the olfactory placode to the hypothalamus. Additionally, our findings implicate the genes, Npn2, Nelf and Dach1, in the regulation of GnRH neurons during Six3 and Six6 disruption.

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