ArticleMolecular neurobiology2018
Haploinsufficiency of SIX3 Abolishes Male Reproductive Behavior Through Disrupted Olfactory Development, and Impairs Female Fertility Through Disrupted GnRH Neuron Migration.
Article in Molecular neurobiology, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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Who cites it
16 citing papers in PubMed, 19 citations in OpenAlex.
- Pan-tissue transcriptomic profiling of dairy cattle.Journal of animal science and biotechnology · 2026Article
- The Transcription Factors Six3 and Six6 in Neuromedin-S Neurons Differentially Affect Circadian Rhythms.Journal of neuroscience research · 2026Article
- Haploinsufficiency of Sox2 causes fewer GnRH neurons and delayed puberty in mice.Endocrinology · 2026Article
- The role ofScience advances · 2024Article
- Deciphering the Transcriptional Landscape of Human Pluripotent Stem Cell-Derived GnRH Neurons: The Role of Wnt Signaling in Patterning the Neural Fate.Stem cells (Dayton, Ohio) · 2022Article
- The role of ciliopathy-associated type 3 adenylyl cyclase in infanticidal behavior in virgin adult male mice.iScience · 2022Article
- Deletion of the homeodomain gene Six3 from kisspeptin neurons causes subfertility in female mice.Molecular and cellular endocrinology · 2022Article
- Circadian Rhythms in the Neuronal Network Timing the Luteinizing Hormone Surge.Endocrinology · 2022Review
- The transcription factors SIX3 and VAX1 are required for suprachiasmatic nucleus circadian output and fertility in female mice.Journal of neuroscience research · 2021Article
- Kiss1 is differentially regulated in male and female mice by the homeodomain transcription factor VAX1.Molecular and cellular endocrinology · 2021Article
- Time-restricted feeding improves the reproductive function of female mice via liver fibroblast growth factor 21.Clinical and translational medicine · 2020Article
- The Homeodomain Transcription Factors Vax1 and Six6 Are Required for SCN Development and Function.Molecular neurobiology · 2020Article
- Deletion of the Homeodomain Protein Six6 From GnRH Neurons Decreases GnRH Gene Expression, Resulting in Infertility.Endocrinology · 2019Article
- Haploinsufficiency of Homeodomain Proteins Six3, Vax1, and Otx2 Causes Subfertility in Mice via Distinct Mechanisms.Neuroendocrinology · 2019Review
- Differential CRE Expression in Lhrh-cre and GnRH-cre Alleles and the Impact on Fertility in Otx2-Flox Mice.Neuroendocrinology · 2019Article
- Determination of Reproductive Competence by Confirming Pubertal Onset and Performing a Fertility Assay in Mice and Rats.Journal of visualized experiments : JoVE · 2018Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.