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

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

  • Science. 2020 Nov 20;370(6519):935-941. doi: 10.1126/science.abb5390.
Christopher Esk # 1,  Dominik Lindenhofer # 1,  Simon Haendeler 1 2,  Roelof A Wester 1,  Florian Pflug 2,  Benoit Schroeder 2,  Joshua A Bagley 1,  Ulrich Elling 1,  Johannes Zuber 3 4,  Arndt von Haeseler 2 5,  Jürgen A Knoblich 6 4
Affiliations

Affiliations

  • 1 Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria.
  • 2 Center for Integrative Bioinformatics Vienna (CIBIV), Max F. Perutz Laboratories, University of Vienna and Medical University of Vienna, VBC, Vienna, Austria.
  • 3 Research Institute of Molecular Pathology (IMP), VBC, Vienna, Austria.
  • 4 Medical University of Vienna, VBC, Vienna, Austria.
  • 5 Bioinformatics and Computational Biology, Faculty of Computer Science, University of Vienna, Vienna, Austria.
  • 6 Institute of Molecular Biotechnology of the Austrian Academy of Science (IMBA), Vienna BioCenter (VBC), Vienna, Austria. juergen.knoblich@imba.oeaw.ac.at.
  • # Contributed equally.
PMID: 33122427 DOI: 10.1126/science.abb5390
Abstract

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.

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