Cerebral organoids model human brain development and microcephaly

Madeline A. Lancaster, Magdalena Renner, Carol-Anne Martin, Daniel Wenzel, Louise S. Bicknell, Matthew E. Hurles, Tessa Homfray, Josef M. Penninger, Andrew P. Jackson and Juergen A. Knoblich ()
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Madeline A. Lancaster: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria
Magdalena Renner: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria
Carol-Anne Martin: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Daniel Wenzel: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria
Louise S. Bicknell: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Matthew E. Hurles: Wellcome Trust Sanger Institute, Cambridge CB10 1SA, UK
Tessa Homfray: St. George’s University, London SW17 0RE, UK
Josef M. Penninger: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria
Andrew P. Jackson: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK
Juergen A. Knoblich: Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna 1030, Austria

Nature, 2013, vol. 501, issue 7467, 373-379

Abstract: Abstract The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem 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 help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.

Date: 2013
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DOI: 10.1038/nature12517

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