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

Christopher Esk(Institute of Molecular Biotechnology), Dominik Lindenhofer(Institute of Molecular Biotechnology), Simon Haendeler(Institute of Molecular Biotechnology), Roelof A. Wester(Institute of Molecular Biotechnology), Florian Pflug(Max Perutz Labs), Benoit Schroeder(Max Perutz Labs), Joshua A. Bagley(Institute of Molecular Biotechnology), Ulrich Elling(Institute of Molecular Biotechnology), Johannes Zuber(Research Institute of Molecular Pathology), Arndt von Haeseler(University of Vienna), Juergen A. Knoblich(Institute of Molecular Biotechnology)
Science
October 29, 2020
10.1126/science.abb5390
Cited by 178Open Access
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Abstract

Functional screen for microcephaly genes Genetic screens are widely used to identify regulators in biological processes. Human screens are currently limited to two-dimensional cell cultures, which lack the ability to score tissue-dependent gene function. Esk et al. combined CRISPR-Cas9 screening with barcoded cellular lineage tracing to enable loss-of-function screening in three-dimensional human cerebral organoid tissue. By testing microcephaly candidate genes, the endoplasmic reticulum was found to control extracellular matrix protein secretion regulating tissue integrity and brain size. This genetic screen in human brain tissue implicates multiple pathways in microcephaly and provides a tool for systematic testing of genes in organoids. Science , this issue p. 935

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