Imprinted genes show differential expression between maternal and paternal alleles as a consequence of epigenetic modification that can result in 'parent-of-origin' effects on phenotypic traits. There is increasing evidence from mouse and human studies that imprinted genes may influence behavior and cognitive functioning. Previous work in girls with Turner syndrome (45,XO) has suggested that there are X-linked parent-of-origin effects on brain development and cognitive functioning, although the interpretation of these data in terms of imprinted gene effects has been questioned. We used a 39,XO mouse model to examine the influence of the parental origin of the X chromosome on cognitive behaviors and expression of X-linked genes in brain. Our findings confirm the existence of X-linked imprinted effects on cognitive processes and identify a new maternally expressed imprinted gene candidate on the X chromosome, Xlr3b, which may be of importance in mediating the behavioral effects.

Ephrin signaling is involved in repulsive and attractive interactions mediating axon guidance and cell-boundary formation in the developing nervous system. As a result of a fortuitous transgene integration event, we have identified here a potential role for EphA5 in the axophilic migration of gonadotropin-releasing hormone (GnRH) neurons from the nasal placode into the brain along ephrinexpressing vomeronasal axons. Transgene integration in the GNR23 mouse line resulted in a 26 kb deletion in chromosome 5, ϳ67 kb 3Ј to Epha5. This induced a profound, region-specific upregulation of EphA5 mRNA and protein expression in the developing mouse brain. The GnRH neurons in GNR23 mice overexpressed EphA5 from embryonic day 11, whereas ephrin A3 and A5 mRNA levels in olfactory neurons were unchanged. The GnRH neurons were found to be slow in commencing their migration from the olfactory placode and also to form abnormal clusters of cells on the olfactory axons, prohibiting their migration out of the nose. As a result, adult hemizygous mice had only 40% of the normal complement of GnRH neurons in the brain, whereas homozygous mice had Ͻ15%. This resulted in infertility in adult female homozygous GNR23 mice, suggesting that some cases of human hypogonadotropic hypogonadism may result from ephrin-related mutations. These data provide evidence for a role of EphA-ephrin signaling in the axophilic migration of the GnRH neurons during embryogenesis.

In the mouse, two large gene families, V1R and V2R, encoding putative pheromone receptors have been described. Studies have suggested a homotypic recognition role for V1Rs and V2Rs during development in the targeting of vomeronasal axons to specific sets of glomeruli in the accessory olfactory bulb (AOB). Analysis of the onset of expression of the V1R and V2R gene families in developing vomeronasal neurons using polymerase chain reaction and in situ hybridization now suggests that a role for these receptors in the organization of axon projections is only likely at the final stages of targeting within the AOB. Surprisingly, our studies reveal expression of a V1Rd receptor in scattered cells within the main olfactory epithelium, suggesting that limited pheromone detection may also take place in this structure. The pheromone sensory neurons of the vomeronasal system and the neuroendocrine gonadotrophin-releasing hormone (GnRH) neurons that regulate fertility both arise from progenitor cells of the nasal placode. The development of these two cell types is intimately linked, and the GnRH neuron population migrates into the forebrain during embryogenesis in close association with a subset of vomeronasal sensory axons; how GnRH neurons recognize this axon subset is unknown. We report selective expression of a V1Ra gene in the clonal NLT GnRH cell line, raising the possibility of a similar role for V1Rs or V2Rs in the directed migration of GnRH neurons. However, no expression of this gene or of other V1Rs and V2Rs is detectable at the cellular level in migrating GnRH neurons in the mouse.

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