title: Disturbances in the positioning, proliferation and apoptosis of neural progenitors contribute to subcortical band heterotopia formation.
abstract: Cortical malformations are commonly associated with intractable epilepsy and other developmental disorders. Our studies utilize the tish rat, a spontaneously occurring genetic model of subcortical band heterotopia (SBH) associated with epilepsy, to evaluate the developmental events underlying SBH formation in the neocortex. Our results demonstrate that Pax6(+) and Tbr2(+) progenitors are mislocalized in tish(+/-) and tish(-/-)- neocortex throughout neurogenesis. In addition, mislocalized tish(-/-) progenitors possess a longer cell cycle than wild type or normally-positioned tish(-/-) progenitors, owing to a lengthened G(2)+M+G(1) time. This mislocalization is not associated with adherens junction breakdown or loss of radial glial polarity in the ventricular zone (VZ), as assessed by immunohistochemistry against phalloidin (to identify F-actin), aPKC-λ and Par3. However, vimentin immunohistochemistry indicates that the radial glial scaffold is disrupted in the region of the tish(-/-) heterotopia. Moreover, lineage tracing experiments using in utero electroporation in tish(-/-) neocortex demonstrate that mislocalized progenitors do not retain contact with the ventricular surface and that ventricular/subventricular zone (SVZ) progenitors produce neurons that migrate into both the heterotopia and cortical plate (CP). Taken together, these findings define a series of developmental errors contributing to SBH formation that differs fundamentally from a primary error in neuronal migration.
authors.affiliation: Department of Neuroscience, University of Virginia, Health Sciences Center, PO Box 801392, Charlottesville, VA 22908, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Fitzgerald
authors.forename: M
authors.initials: M
authors.lastname: Covio
authors.forename: K S
authors.initials: KS
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology; D016764:Cell Polarity / Q000502:physiology; D049109:Cell Proliferation; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000473:pathology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D019579:Neocortex / Q000002:abnormalities* / Q000473:pathology; D058953:Neural Stem Cells / Q000473:pathology*; D055495:Neurogenesis / Q000502:physiology*; D051381:Rats