Cell-type specific defects in PTEN-mutant cortical organoids converge on abnormal circuit activity.

Autor:	Pigoni M; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Uzquiano A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Paulsen B; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Kedaigle AJ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Yang SM; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Symvoulidis P; McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA., Adiconis X; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Velasco S; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Sartore R; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Kim K; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Tucewicz A; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Tropp SY; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA., Tsafou K; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Jin X; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Society of Fellows, Harvard University, Cambridge, MA 02138, USA., Barrett L; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Chen F; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Boyden ES; McGovern Institute for Brain Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.; MIT Center for Neurobiological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.; Harvard-MIT Health Sciences & Technology Program (HST), Harvard Medical School, Boston, MA 02115, USA.; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.; Howard Hughes Medical Institute, MIT, Cambridge, MA 02138, USA.; Department of Brain of Cognitive Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.; Department of Media Arts and Sciences, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.; Department of Biological Engineering, Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA., Regev A; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Levin JZ; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.; Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA., Arlotta P; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
Jazyk:	angličtina
Zdroj:	Human molecular genetics [Hum Mol Genet] 2023 Sep 05; Vol. 32 (18), pp. 2773-2786.
DOI:	10.1093/hmg/ddad107
Abstrakt:	De novo heterozygous loss-of-function mutations in phosphatase and tensin homolog (PTEN) are strongly associated with autism spectrum disorders; however, it is unclear how heterozygous mutations in this gene affect different cell types during human brain development and how these effects vary across individuals. Here, we used human cortical organoids from different donors to identify cell-type specific developmental events that are affected by heterozygous mutations in PTEN. We profiled individual organoids by single-cell RNA-seq, proteomics and spatial transcriptomics and revealed abnormalities in developmental timing in human outer radial glia progenitors and deep-layer cortical projection neurons, which varied with the donor genetic background. Calcium imaging in intact organoids showed that both accelerated and delayed neuronal development phenotypes resulted in similar abnormal activity of local circuits, irrespective of genetic background. The work reveals donor-dependent, cell-type specific developmental phenotypes of PTEN heterozygosity that later converge on disrupted neuronal activity. (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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