4.5 Article

DISTURBANCES IN THE POSITIONING, PROLIFERATION AND APOPTOSIS OF NEURAL PROGENITORS CONTRIBUTE TO SUBCORTICAL BAND HETEROTOPIA FORMATION

期刊

NEUROSCIENCE
卷 176, 期 -, 页码 455-471

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PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2010.12.003

关键词

Tbr2; Pax6; epilepsy; intermediate progenitor; migration; radial glia

资金

  1. National Institutes of Health [NS34124, GM08238]

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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 Tbr(2+) 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-lambda 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. (C) 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

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