Loss of POGZ alters neural differentiation of human embryonic stem cells

Lu Deng; Sandra P. Mojica-Perez; Ruth D. Azaria; Mark Schultz; Jack M. Parent; Wei Niu

doi:10.1016/j.mcn.2022.103727

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Loss of POGZ alters neural differentiation of human embryonic stem cells

Journal article

Open access

Peer reviewed

Loss of POGZ alters neural differentiation of human embryonic stem cells

Lu Deng, Sandra P. Mojica-Perez, Ruth D. Azaria, Mark Schultz, Jack M. Parent and Wei Niu

Molecular and cellular neurosciences, Vol.120, pp.103727-103727

05/2022

DOI: 10.1016/j.mcn.2022.103727

PMCID: PMC9549529

PMID: 35367590

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https://www.ncbi.nlm.nih.gov/pmc/articles/9549529View

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Abstract

POGZ is a pogo transposable element derived protein with multiple zinc finger domains. Many de novo loss-of-function (LoF) variants of the POGZ gene are associated with autism and other neurodevelopmental disorders. However, the role of POGZ in human cortical development remains poorly understood. Here we generated multiple POGZ LoF lines in H9 human embryonic stem cells (hESCs) using CRISPR/CAS9 genome editing. These lines were then differentiated into neural structures, similar to those found in early to mid-fetal human brain, a critical developmental stage for studying disease mechanisms of neurodevelopmental disorders. We found that the loss of POGZ reduced neural stem cell proliferation in excitatory cortex-patterned neural rosettes, structures analogous to the cortical ventricular zone in human fetal brain. As a result, fewer intermediate progenitor cells and early born neurons were generated. In addition, neuronal migration from the apical center to the basal surface of neural rosettes was perturbed due to the loss of POGZ. Furthermore, cortical-like excitatory neurons derived from multiple POGZ homozygous knockout lines exhibited a more simplified dendritic architecture compared to wild type lines. Our findings demonstrate how POGZ regulates early neurodevelopment in the context of human cells, and provide further understanding of the cellular pathogenesis of neurodevelopmental disorders associated with POGZ variants. •POGZ regulates NSC proliferation and lineage progression in human cortical rosettes.•POGZ depletion impairs migration of developing neurons.•Loss of POGZ reduces dendritic complexity of cortical-like excitatory neurons.

Autism spectrum disorders

CRISPR/CAS9 genome editing

Neurodevelopment

Neurodevelopmental disorders

Neuronal differentiation

Neuronal migration

Details

Title: Subtitle: Loss of POGZ alters neural differentiation of human embryonic stem cells
Creators: Lu Deng - University of Michigan
Sandra P. Mojica-Perez - University of Michigan
Ruth D. Azaria - University of Michigan Medical School
Mark Schultz - University of Michigan Medical School
Jack M. Parent - University of Michigan
Wei Niu - University of Michigan
Resource Type: Journal article
Publication Details: Molecular and cellular neurosciences, Vol.120, pp.103727-103727
DOI: 10.1016/j.mcn.2022.103727
PMID: 35367590
PMCID: PMC9549529
NLM abbreviation: Mol Cell Neurosci
ISSN: 1044-7431
eISSN: 1095-9327
Publisher: Elsevier Inc
Language: English
Date published: 05/2022
Academic Unit: Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
Record Identifier: 9984366366802771

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