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Abstract
The paired-box 6 (PAX6) gene encodes a highly-conserved transcription factor necessary for normal development of both the eye and the central nervous system. PAX6 has been implicated in aspects of central nervous system development such as patterning, regionalization, and the formation of neural circuits; however, PAX6s role in the adult brain has yet to be described. Heterozygous loss-of-function mutations to PAX6 result in a disorder called aniridia in humans and the Small eye phenotype in mice. Aniridia is a congenital and progressive disorder most well-known for its ocular phenotypes including absence or hypoplasia of the iris, for which it is named. Although the disorder is best-known for its ocular phenotypes, the condition has a several other abnormalities, which are only recently emerging as prominent features of the disorder. These include neural, sensory, cognitive, and auditory processing abnormalities. These abnormalities are likely caused by either developmental deficits within the brain or maintenance related problems in the adult brain. There has been little homogeneity within brain-related aniridia research, and a wide-variety of structural changes with much variation across the population have been described. The work presented here aimed to investigate the structural abnormalities in the brains of both aniridia patients and our mouse model of the disorder using high-resolution structural MRI. Through analysis of a new cohort of aniridia patients, representing a variety of aniridia-causing mutations, we showed that the structural changes to the aniridia brains are highly variable and less severe than previously reported. We also investigated structural changes in the brain of our mouse model of the disorder, Small eye (Pax6SeyNeu/+), and found similar results using structural MRI and histology. Our mice had strikingly normal brains with all structures still present and only slight reductions in volume and commissure thickness. We did, however, discover an age-related change in the plasticity of the Pax6SeyNeu/+ brains, suggesting a role of Pax6 during adult brain neurogenesis and maintenance. Together, these studies contribute to our understanding of the role of PAX6 in both normal development and maintenance of the adult mammalian brain, and aid in understanding the neurological phenotypes of aniridia patients.