| Title: | "Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration" |
| Author(s): | Pandolfi EC; Hoffmann HM; Schoeller EL; Gorman MR; Mellon PL; |
| Address: | "Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0674, USA. Center for Circadian Biology, University of California, San Diego, La Jolla, CA, 92093, USA. Department of Psychology, University of California, San Diego, La Jolla, CA, 92093, USA. Department of Reproductive Medicine, Center for Reproductive Science and Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093-0674, USA. pmellon@ucsd.edu. Center for Circadian Biology, University of California, San Diego, La Jolla, CA, 92093, USA. pmellon@ucsd.edu" |
| DOI: | 10.1007/s12035-018-1013-0 |
| ISSN/ISBN: | 1559-1182 (Electronic) 0893-7648 (Print) 0893-7648 (Linking) |
| Abstract: | "Mating behavior in males and females is dependent on olfactory cues processed through both the main olfactory epithelium (MOE) and the vomeronasal organ (VNO). Signaling through the MOE is critical for the initiation of male mating behavior, and the loss of MOE signaling severely compromises this comportment. Here, we demonstrate that dosage of the homeodomain gene Six3 affects the degree of development of MOE but not the VNO. Anomalous MOE development in Six3 heterozygote mice leads to hyposmia, specifically disrupting male mounting behavior by impairing detection of volatile female estrus pheromones. Six3 is highly expressed in the MOE, main olfactory bulb (MOB), and hypothalamus; all regions essential in the proper migration of the gonadotropin-releasing hormone (GnRH) neurons, a key reproductive neuronal population that migrates along olfactory axons from the developing nose into the brain. Interestingly, we find that the reduction in Six3 expression in Six3 heterozygote mice compromises development of the MOE and MOB, resulting in mis-migration of GnRH neurons due to improper olfactory axon targeting. This reduction in the hypothalamic GnRH neuron population, by 45% in adulthood, leads to female subfertility, but does not impact male hormone levels, suggesting that male infertility is not related to GnRH neuron numbers, but exclusively linked to abnormal olfaction. We here determine that Six3 is haploinsufficient for MOE development, GnRH neuron migration, and fertility, and represents a novel candidate gene for Kallmann syndrome, a form of inherited infertility" |
| Keywords: | "Alleles Animals Cell Count *Cell Movement Estrous Cycle Eye Proteins/*genetics/metabolism Female *Fertility Gonadotropin-Releasing Hormone/*metabolism Haploinsufficiency/*genetics Heterozygote Homeodomain Proteins/*genetics/metabolism Male Mice, Inbred C5;" |
| Notes: | "MedlinePandolfi, Erica C Hoffmann, Hanne M Schoeller, Erica L Gorman, Michael R Mellon, Pamela L eng R25 GM083275/GM/NIGMS NIH HHS/ R00 HD084759/HD/NICHD NIH HHS/ T32 HD007203/HD/NICHD NIH HHS/ P42 ES010337/ES/NIEHS NIH HHS/ P50 HD012303/NH/NIH HHS/ P30 CA023100/CA/NCI NIH HHS/ K99 HD084759/HD/NICHD NIH HHS/ R25 GM083275/NH/NIH HHS/ R01 HD082567/NH/NIH HHS/ T32 HD007203/NH/NIH HHS/ F31 HD089652/HD/NICHD NIH HHS/ R01 HD072754/HD/NICHD NIH HHS/ R01 HD082567/HD/NICHD NIH HHS/ P42 ES101337/NH/NIH HHS/ T32 DK007044/DK/NIDDK NIH HHS/ n/a/Lalor Foundation/ P30 DK063491/NH/NIH HHS/ P30 DK063491/DK/NIDDK NIH HHS/ P30 CA023100/NH/NIH HHS/ T32 DK007044/NH/NIH HHS/ K99 HD084759/NH/NIH HHS/ P50 HD012303/HD/NICHD NIH HHS/ F31 HD098652/NH/NIH HHS/ R24 HD102061/HD/NICHD NIH HHS/ R01 HD072754/NH/NIH HHS/ 2018/03/29 Mol Neurobiol. 2018 Nov; 55(11):8709-8727. doi: 10.1007/s12035-018-1013-0. Epub 2018 Mar 27" |
