A human tissue screen identifies a regulator of ER secretion as a brain-size determinant.

Autor: Esk C; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Lindenhofer D; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Haendeler S; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria.; Center for Integrative Bioinformatics Vienna (CIBIV), Max F. Perutz Laboratories, University of Vienna and Medical University of Vienna, VBC, Vienna, Austria., Wester RA; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Pflug F; Center for Integrative Bioinformatics Vienna (CIBIV), Max F. Perutz Laboratories, University of Vienna and Medical University of Vienna, VBC, Vienna, Austria., Schroeder B; Center for Integrative Bioinformatics Vienna (CIBIV), Max F. Perutz Laboratories, University of Vienna and Medical University of Vienna, VBC, Vienna, Austria., Bagley JA; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Elling U; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria., Zuber J; Research Institute of Molecular Pathology (IMP), VBC, Vienna, Austria.; Medical University of Vienna, VBC, Vienna, Austria., von Haeseler A; Center for Integrative Bioinformatics Vienna (CIBIV), Max F. Perutz Laboratories, University of Vienna and Medical University of Vienna, VBC, Vienna, Austria.; Bioinformatics and Computational Biology, Faculty of Computer Science, University of Vienna, Vienna, Austria., Knoblich JA; Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria. juergen.knoblich@imba.oeaw.ac.at.; Medical University of Vienna, VBC, Vienna, Austria.
Jazyk: angličtina
Zdroj: Science (New York, N.Y.) [Science] 2020 Nov 20; Vol. 370 (6519), pp. 935-941. Date of Electronic Publication: 2020 Oct 29.
DOI: 10.1126/science.abb5390
Abstrakt: Loss-of-function (LOF) screens provide a powerful approach to identify regulators in biological processes. Pioneered in laboratory animals, LOF screens of human genes are currently restricted to two-dimensional cell cultures, which hinders the testing of gene functions requiring tissue context. Here, we present CRISPR-lineage tracing at cellular resolution in heterogeneous tissue (CRISPR-LICHT), which enables parallel LOF studies in human cerebral organoid tissue. We used CRISPR-LICHT to test 173 microcephaly candidate genes, revealing 25 to be involved in known and uncharacterized microcephaly-associated pathways. We characterized IER3IP1 , which regulates the endoplasmic reticulum (ER) function and extracellular matrix protein secretion crucial for tissue integrity, the dysregulation of which results in microcephaly. Our human tissue screening technology identifies microcephaly genes and mechanisms involved in brain-size control.
(Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze: MEDLINE
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