Sex-Difference in Olfactory Interhemispheric Malformation Caused by Pax6 Haploinsufficiency

Sex differences are increasingly recognized as critical factors influencing the onset and manifestation of various neurodevelopmental disorders, including autism spectrum disorder (ASD). Among ASD-associated genes, Pax6, which encodes a transcription factor, has been implicated in sex-dependent phenotypes when mutated. The anterior commissure (AC), a major commissural pathway involved in higher cognitive and social functions, exhibits structural abnormalities both in individuals with ASD and in those carrying Pax6 mutations. Anatomically, the AC consists of two principal fiber bundles: the anterior limb (aAC), connecting the olfactory bulbs and anterior olfactory nucleus, and the posterior limb (pAC), connecting the piriform cortex and amygdaloid regions, both converging at the midline. In this study, we investigated sex-specific structural abnormalities of the AC in Pax6 mutant mice. Analysis of horizontal and sagittal AC sections revealed that Pax6 haploinsufficiency in mice induces abnormal de-fasciculation in the aAC and aberrant intermingling of aAC and pAC fibers at the midline. Notably, Pax6 mutant females exhibited more diverse phenotypes. These females showed a pronounced reduction in overall AC size and disruptions in pAC shape regularity, likely due to a more severe disruption of the boundary between the aAC and pAC axon bundles. These sex-dependent alterations in AC morphology may contribute to the sexually dimorphic phenotypes observed in various neurodevelopmental disorders, including autism spectrum disorder.