Functional Genomic Screen of Human Stem Cell Differentiation Reveals Pathways Involved in Neurodevelopment and Neurodegeneration

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2013 Jul 10

PMID 23836664

Citations 7

Authors

Ying Zhang

Vincent P Schulz

Brian D Reed

Zheng Wang

Xinghua Pan

Jessica Mariani

Ghia Euskirchen

Michael P Snyder

Flora M Vaccarino

Natalia Ivanova

Sherman M Weissman

Anna M Szekely

Affiliations

Soon will be listed here.

Abstract

Human embryonic stem cells (hESCs) can be induced and differentiated to form a relatively homogeneous population of neuronal precursors in vitro. We have used this system to screen for genes necessary for neural lineage development by using a pooled human short hairpin RNA (shRNA) library screen and massively parallel sequencing. We confirmed known genes and identified several unpredicted genes with interrelated functions that were specifically required for the formation or survival of neuronal progenitor cells without interfering with the self-renewal capacity of undifferentiated hESCs. Among these are several genes that have been implicated in various neurodevelopmental disorders (i.e., brain malformations, mental retardation, and autism). Unexpectedly, a set of genes mutated in late-onset neurodegenerative disorders and with roles in the formation of RNA granules were also found to interfere with neuronal progenitor cell formation, suggesting their functional relevance in early neurogenesis. This study advances the feasibility and utility of using pooled shRNA libraries in combination with next-generation sequencing for a high-throughput, unbiased functional genomic screen. Our approach can also be used with patient-specific human-induced pluripotent stem cell-derived neural models to obtain unparalleled insights into developmental and degenerative processes in neurological or neuropsychiatric disorders with monogenic or complex inheritance.

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