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      Cerebral organoids model human brain development and microcephaly

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          Abstract

          The complexity of the human brain has made it difficult to study many brain disorders in model organisms, and highlights the need for an in vitro model of human brain development. We have developed a human pluripotent stem cell-derived 3D organoid culture system, termed cerebral organoid, which develops various discrete though interdependent brain regions. These include cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNAi and patient-specific iPS cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could explain the disease phenotype. Our data demonstrate that 3D organoids can recapitulate development and disease of even this most complex human tissue.

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          Most cited references41

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          The cell biology of neurogenesis.

          During the development of the mammalian central nervous system, neural stem cells and their derivative progenitor cells generate neurons by asymmetric and symmetric divisions. The proliferation versus differentiation of these cells and the type of division are closely linked to their epithelial characteristics, notably, their apical-basal polarity and cell-cycle length. Here, we discuss how these features change during development from neuroepithelial to radial glial cells, and how this transition affects cell fate and neurogenesis.
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            Electroporation and RNA interference in the rodent retina in vivo and in vitro.

            The large number of candidate genes made available by comprehensive genome analysis requires that relatively rapid techniques for the study of function be developed. Here, we report a rapid and convenient electroporation method for both gain- and loss-of-function studies in vivo and in vitro in the rodent retina. Plasmid DNA directly injected into the subretinal space of neonatal rodent pups was taken up by a significant fraction of exposed cells after several pulses of high voltage. With this technique, GFP expression vectors were efficiently transfected into retinal cells with little damage to the operated pups. Transfected GFP allowed clear visualization of cell morphologies, and the expression persisted for at least 50 days. DNA-based RNA interference vectors directed against two transcription factors important in photoreceptor development led to photoreceptor phenotypes similar to those of the corresponding knockout mice. Reporter constructs carrying retinal cell type-specific promoters were readily introduced into the retina in vivo, where they exhibited the appropriate expression patterns. Plasmid DNA was also efficiently transfected into retinal explants in vitro by high-voltage pulses.
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              OSVZ progenitors of human and ferret neocortex are epithelial-like and expand by integrin signaling.

              A major cause of the cerebral cortex expansion that occurred during evolution is the increase in subventricular zone (SVZ) progenitors. We found that progenitors in the outer SVZ (OSVZ) of developing human neocortex retain features of radial glia, in contrast to rodent SVZ progenitors, which have limited proliferation potential. Although delaminating from apical adherens junctions, OSVZ progenitors maintained a basal process contacting the basal lamina, a canonical epithelial property. OSVZ progenitor divisions resulted in asymmetric inheritance of their basal process. Notably, OSVZ progenitors are also found in the ferret, a gyrencephalic nonprimate. Functional disruption of integrins, expressed on the basal process of ferret OSVZ progenitors, markedly decreased the OSVZ progenitor population size, but not that of other, process-lacking SVZ progenitors, in slice cultures of ferret neocortex. Our findings suggest that maintenance of this epithelial property allows integrin-mediated, repeated asymmetric divisions of OSVZ progenitors, providing a basis for neocortical expansion.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                18 October 2013
                28 August 2013
                19 September 2013
                19 March 2014
                : 501
                : 7467
                : 10.1038/nature12517
                Affiliations
                [1 ]IMBA - Institute of Molecular Biotechnology of the Austrian Academy of Science, Vienna 1030, Austria
                [2 ]MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK
                [3 ]Wellcome Trust Sanger Institute, Cambridge, UK
                [4 ]Department of Clinical Genetics, St. George’s University, London, UK
                Author notes
                Correspondence and requests for materials should be addressed to J.A.K. ( juergen.knoblich@ 123456imba.oeaw.ac.at ).

                Author Contributions: M.A.L and J.A.K. conceived of the project and experimental design and wrote the manuscript. M.A.L. performed experiments and analyzed data. M.R., C.-A.M., and D.W. performed experiments and analyzed data under supervision of J.A.K., J.M.P., and A.P.J. L.S.B., M.H., and T.H. performed patient diagnosis and provided MRIs coordinated by A.P.J. J.A.K. directed and supervised the project.

                Article
                EMS54265
                10.1038/nature12517
                3817409
                23995685
                26219c2d-837a-4063-a16e-3eee2c6e0222

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                History
                Funding
                Funded by: Austrian Science Fund FWF :
                Award ID: Z 153-B09 || FWF_
                Funded by: Austrian Science Fund FWF :
                Award ID: I 552-B19 || FWF_
                Funded by: European Research Council :
                Award ID: 250342 || ERC_
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