Brain Folds and the Extracellular Matrix: Lessons from Brain Organoids

ORAL  · Invited

Abstract

Neurodevelopmental brain disorders include a spectrum of diseases, ranging from brain malformations, such as microcephaly (small brain) and lissencephaly (smooth brain), through different forms of epilepsy, to intellectual disability, autism spectrum disorders, and schizophrenia. Our studies focused on haploinsufficient mutations in LIS1 that result in lissencephaly. Using different brain organoid models, we detected changes in the matrisome, which includes components of the extracellular matrix (ECM) and their modulating enzymes. We identified the molecular mechanisms involved in changing gene expression and demonstrated how the physical properties of the organoids change. We believe that our studies are important for understanding how the brain folds during embryonic development and what goes wrong in case of diseases.

*O.R. is an incumbent of the Berstein-Mason professorial chair of Neurochemistry and the Head of M. Judith Ruth Institute for Preclinical Brain Research. Our research has been supported by a research grant from Ethel Lena Levy, the Selsky Memory Research Project, the Advantage Trust, the William and Joan Brodsky Foundation and the Edward F. Anixter Family Foundation, the Helen and Martin Kimmel Institute for Stem Cell Research, the Nella and Leon Benoziyo Center for Neurological Diseases, the David and Fela Shapell Family Center for Genetic Disorders Research, the Brenden-Mann Women's Innovation Impact Fund, The Irving B. Harris Fund for New Directions in Brain Research, the Irving Bieber, M.D. and Toby Bieber, M.D. Memorial Research Fund, The Leff Family, Barbara & Roberto Kaminitz, Sergio & Sônia Lozinsky, Debbie Koren, Jack, and Lenore Lowenthal, and the Dears Foundation, a research grant from the Weizmann SABRA - Yeda-Sela - WRC Program, the Estate of Emile Mimran, and The Maurice and Vivienne Wohl Biology Endowment Canadian Institutes of Health Research (CIHR), the International Development Research Centre (IDRC), the Israel Science Foundation (ISF) and the Azrieli Foundation (2397/18), the ISF grant (545/21), and the United States-Israel Binational Science Foundation (BSF; Grant No. 2017006).

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Publication: Maayan Karlinski, Irit Sagi, Amnon Buxboim, Orly Reiner (in preparation). ECM changes and Mechanical Properties of LIS1-/+ Brain Organoids.

Aditya Kshirsagar, Anna Gorelik, Tsviya Olender, Tamar Sapir, Daisuke Tsuboi, Irit Rosenhek-Goldian, Sergey Malitsky, Maxim Itkin, Amir Argoetti, Yael Mandel-Gutfreund, Sidney R. Cohen, Jacob Hanna, Igor Ulitsky, Kozo Kaibuchi, Orly Reiner. LIS1 RNA-binding orchestrates the mechanosensitive properties of embryonic stem cells in AGO2-dependent and independent ways. bioRxiv 2022.03.08.483407; doi: https://doi.org/10.1101/2022.03.08.483407

Karzbrun E, Kshirsagar A, Cohen SR, Hanna JH, Reiner O. Human Brain Organoids on a Chip Reveal the Physics of Folding. Nat Phys. 2018 May;14(5):515-522. doi: 10.1038/s41567-018-0046-7. Epub 2018 Feb 19. PubMed PMID: 29760764; PubMed Central PMCID: PMC5947782

Presenters

  • Orly Reiner

    • Weizmann Institute of Science

Authors

  • Orly Reiner

    • Weizmann Institute of Science