I. Asymmetric Cell Division; From Drosophila to Humans
II. Modeling Human Brain Development and Disease in Stem Cell Derived 3D
Part I: Asymmetric Cell Division; From Drosophila to Humans
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Dr. Knoblich begins his talk by explaining the key role that asymmetric cell division plays in development of the human brain. During mammalian brain development, neuronal progenitor cells initially divide symmetrically to increase their numbers. Later they divide asymmetrically to produce one progenitor cell and one (or two) cells which will terminally differentiate to become neurons. What determines which daughter cell will become which? Working in Drosophila, Knoblich and others elucidated a signaling pathway in which Par proteins are asymmetrically localized before cell division. This recruits a complex of proteins which defines the orientation of the mitotic spindle and causes the localization of Numb protein at one pole of the cell. Upon cell division, only one daughter cell will inherit Numb protein and this ultimately will determine the fate of the daughter cells. Interestingly, this signaling pathway is conserved from insects to mammals, however, Knoblich found an important difference that may explain why humans have many more cortical neurons than mice.
In his second talk, Knoblich describes experiments in his lab to develop 3 dimensional brain organoids from human pluripotent stem cells. While studying the development of rodent brains has proved extremely useful, there are some important developmental differences that require human tissue for investigation. In addition, some diseases such as microcephaly cannot be modeled in mice. Knoblich and his colleagues have developed cerebral organoids that mimic early human brain development and can be used to model neurodevelopmental disorders. They have also been able to generate separate organoids from various regions of the human brain and then fuse them and follow the migration of live neurons between these parts, opening the path to many more studies of neuronal development.
Jürgen Knoblich is a senior scientist and deputy director of the Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) and an Adjunct Professor at the Medical University of Vienna. Knoblich’s lab is interested in understanding how the complexity of the human brain is generated from progenitor and stem cells during development. To address this question, they study brain development in Drosophila, mice and in 3D human stem cell derived brain organoids.
Knoblich completed his PhD studies in the Friedrich Miescher Laboratory of the Max Planck Institute in Tubingen, Germany. He was a post-doctoral fellow at the University of California, San Francisco before returning to Europe in 1997 to join the Institute for Molecular Pathology in Vienna. In 2004, Knoblich moved to the IMBA, becoming Deputy Director in 2005.
Knoblich is an elected member of the Austrian Academy of Sciences and the EMBO Council. He has received numerous awards for his research including the Wittgenstein Prize, the Schroedinger Award and the Sir Hans Krebs Medal.
Learn more about Knoblich’s research here.
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Knoblich JA, Jan LY, Jan YN. (1995) Asymmetric segregation of Numb and Prospero during cell division. Nature. 377(6550):624-7.
Chenn A, McConnell SK. (1995) Cleavage orientation and the asymmetric inheritance of Notch1 immunoreactivity in mammalian neurogenesis. Cell. 82(4):631-41.
Kraut R, Chia W, Jan LY, Jan YN, Knoblich JA.(1996) Role of inscuteable in orienting asymmetric cell divisions in Drosophila. Nature. 383(6595):50-5.
Knoblich JA, Jan LY, Jan YN. (1997) The N terminus of the Drosophila Numb protein directs membrane association and actin-dependent asymmetric localization. Proc Natl Acad Sci U S A. 94(24):13005-10.
Schaefer M, Shevchenko A, Shevchenko A, Knoblich JA. (2000) A protein complex containing Inscuteable and the Galpha-binding protein Pins orients asymmetric cell divisions in Drosophila. Curr Biol. 10(7):353-62.
Bowman SK, Neumüller RA, Novatchkova M, Du Q, Knoblich JA. (2006) The Drosophila NuMA Homolog Mud regulates spindle orientation in asymmetric cell division. Dev Cell.10(6):731-42.
Wirtz-Peitz F, Nishimura T, Knoblich JA. (2008) Linking cell cycle to asymmetric division: Aurora-A phosphorylates the Par complex to regulate Numb localization. Cell. 135(1):161-73.
Postiglione MP, Jüschke C, Xie Y, Haas GA, Charalambous C, Knoblich JA. (2011) Mouse inscuteable induces apical-basal spindle orientation to facilitate intermediate progenitor generation in the developing neocortex. Neuron. 72(2):269-84.
Lancaster MA, Renner M, Martin CA, Wenzel D, Bicknell LS, Hurles ME, Homfray T, Penninger JM, Jackson AP, Knoblich JA. (2013) Cerebral organoids model human brain development and microcephaly. Nature. 501(7467):373-9.
Lancaster MA, Knoblich JA. (2014) Generation of cerebral organoids from human pluripotent stem cells. Nat Protoc. 9(10):2329-40.
Bagley JA, Reumann D, Bian S, Lévi-Strauss J, Knoblich JA. (2017) Fused cerebral organoids model interactions between brain regions. Nat Methods. 14(7):743-751.
Renner M, Lancaster MA, Bian S, Choi H, Ku T, Peer A, Chung K, Knoblich JA. (2017)
Self-organized developmental patterning and differentiation in cerebral organoids. EMBO J. 36(10):1316-1329.