Murine pluripotent stem cells with a homozygous knockout of Foxg1 show reduced differentiation towards cortical progenitors in vitro

Mall, Eva Maria; Herrmann, Doris; Niemann, Heiner

doi:10.1016/j.scr.2017.10.012

Cited by 10 publications

(4 citation statements)

References 56 publications

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“…Mutations in FOXG1 are causal of a rare neurodevelopmental disorder (FOXG1 syndrome) that results in abnormal brain function. Studies showed that complete loss of foxg1 in mice is post-natally lethal, while homozygous knockout of the gene in differentiating cells leads to generation of significantly smaller embryoid bodies ( Martynoga et al, 2005 ; Mall et al, 2017 ; Hettige et al, 2019 ). It has been shown that during early brain development, FOXG1 can directly control levels of PAX6 and inhibit the premature differentiation of neurons ( Manuel et al, 2011 ; Patriarchi et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

A high ratio of linoleic acid (n-6 PUFA) to alpha-linolenic acid (n-3 PUFA) adversely affects early stage of human neuronal differentiation and electrophysiological activity of glutamatergic neurons in vitro

Dec

Alsaqati

Morgan

et al. 2023

Front. Cell Dev. Biol.

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Introduction: There is a growing interest in the possibility of dietary supplementation with polyunsaturated fatty acids (PUFAs) for treatment and prevention of neurodevelopmental and neuropsychiatric disorders. Studies have suggested that of the two important classes of polyunsaturated fatty acids, omega-6 (n-6) and omega-3 (n-3), n-3 polyunsaturated fatty acids support brain development and function, and when used as a dietary supplement may have beneficial effects for maintenance of a healthy brain. However, to date epidemiological studies and clinical trials on children and adults have been inconclusive regarding treatment length, dosage and use of specific n-3 polyunsaturated fatty acids. The aim of this study is to generate a simplified in vitro cell-based model system to test how different n-6 to n-3 polyunsaturated fatty acids ratios affect human-derived neurons activity as a cellular correlate for brain function and to probe the mechanism of their action.Methods: All experiments were performed by use of human induced pluripotent stem cells (iPSCs). In this study, we examined the effect of different ratios of linoleic acid (n-6) to alpha-linolenic acid in cell growth medium on induced pluripotent stem cell proliferation, generation of neuronal precursors and electrophysiology of cortical glutamatergic neurons by multielectrode array (MEA) analysis.Results: This study shows that at a n-6:n-3 ratio of 5:1 polyunsaturated fatty acids induce stem cell proliferation, generating a large increase in number of cells after 72 h treatment; suppress generation of neuronal progenitor cells, as measured by decreased expression of FOXG1 and Nestin in neuronal precursor cells (NPC) after 20 days of development; and disrupt neuronal activity in vitro, increasing spontaneous neuronal firing, reducing synchronized bursting receptor subunits. We observed no significant differences for neuronal precursor cells treated with ratios 1:3 and 3:1, in comparison to 1:1 control ratio, but higher ratios of n-6 to n-3 polyunsaturated fatty acids adversely affect early stages of neuronal differentiation. Moreover, a 5:1 ratio in cortical glutamatergic neurons induce expression of GABA receptors which may explain the observed abnormal electrophysiological activity.

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Section: Discussionmentioning

confidence: 99%

A high ratio of linoleic acid (n-6 PUFA) to alpha-linolenic acid (n-3 PUFA) adversely affects early stage of human neuronal differentiation and electrophysiological activity of glutamatergic neurons in vitro

Dec

Alsaqati

Morgan

et al. 2023

Front. Cell Dev. Biol.

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“…[168][169][170] Cortical neurons generated from FOXG1deficient mouse pluripotent stem cells express reduced level of vGluTt1. 171 Similarly, patient-derived iPSCs and from mice hemizygous for FOXG1 deletion display reduced vGlut1. 172 With regard to astrocytes-expressing MeCP2 in MeCP2lacking astrocytes results in the elevation of vGlut1 in MeCP2-deficient neurons and restoration of normal dendritic morphology.…”

Section: Potential Common Effectorsmentioning

confidence: 99%

“…168–170 Cortical neurons generated from FOXG1-deficient mouse pluripotent stem cells express reduced level of vGluTt1. 171 Similarly, patient-derived iPSCs and from mice hemizygous for FOXG1 deletion display reduced vGlut1. 172…”

Section: Potential Common Effectorsmentioning

confidence: 99%

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

D’Mello

2023

Exp Biol Med (Maywood)

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Rett syndrome is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl-CpG binding protein-2 (MeCP2) gene that is characterized by epilepsy, intellectual disability, autistic features, speech deficits, and sleep and breathing abnormalities. Neurologically, patients with all three disorders display microcephaly, aberrant dendritic morphology, reduced spine density, and an imbalance of excitatory/inhibitory signaling. Loss-of-function mutations in the cyclin-dependent kinase-like 5 (CDKL5) and FOXG1 genes also cause similar behavioral and neurobiological defects and were referred to as congenital or variant Rett syndrome. The relatively recent realization that CDKL5 deficiency disorder (CDD), FOXG1 syndrome, and Rett syndrome are distinct neurodevelopmental disorders with some distinctive features have resulted in separate focus being placed on each disorder with the assumption that distinct molecular mechanisms underlie their pathogenesis. However, given that many of the core symptoms and neurological features are shared, it is likely that the disorders share some critical molecular underpinnings. This review discusses the possibility that deregulation of common molecules in neurons and astrocytes plays a central role in key behavioral and neurological abnormalities in all three disorders. These include KCC2, a chloride transporter, vGlut1, a vesicular glutamate transporter, GluD1, an orphan-glutamate receptor subunit, and PSD-95, a postsynaptic scaffolding protein. We propose that reduced expression or activity of KCC2, vGlut1, PSD-95, and AKT, along with increased expression of GluD1, is involved in the excitatory/inhibitory that represents a key aspect in all three disorders. In addition, astrocyte-derived brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and inflammatory cytokines likely affect the expression and functioning of these molecules resulting in disease-associated abnormalities.

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“…Other models of complete loss of Foxg1 have also been investigated. In a homozygous knockout neuronal cell line, embryoid bodies (EBs) derived from induced pluripotent stem cells (iPSCs) were significantly smaller (88), supporting a role for Foxg1 in cell survival. In vivo adult neurogenesis models support this finding.…”

Section: Foxg1 Dose and Cell Survivalmentioning

confidence: 99%

FOXG1 Dose in Brain Development

Hettige

Ernst

2019

Front. Pediatr.

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Brain development is a highly regulated process that involves the precise spatio-temporal activation of cell signaling cues. Transcription factors play an integral role in this process by relaying information from external signaling cues to the genome. The transcription factor Forkhead box G1 (FOXG1) is expressed in the developing nervous system with a critical role in forebrain development. Altered dosage of FOXG1 due to deletions, duplications, or functional gain- or loss-of-function mutations, leads to a complex array of cellular effects with important consequences for human disease including neurodevelopmental disorders. Here, we review studies in multiple species and cell models where FOXG1 dose is altered. We argue against a linear, symmetrical relationship between FOXG1 dosage states, although FOXG1 levels at the right time and place need to be carefully regulated. Neurodevelopmental disease states caused by mutations in FOXG1 may therefore be regulated through different mechanisms.

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Murine pluripotent stem cells with a homozygous knockout of Foxg1 show reduced differentiation towards cortical progenitors in vitro

Cited by 10 publications

References 56 publications

A high ratio of linoleic acid (n-6 PUFA) to alpha-linolenic acid (n-3 PUFA) adversely affects early stage of human neuronal differentiation and electrophysiological activity of glutamatergic neurons in vitro

A high ratio of linoleic acid (n-6 PUFA) to alpha-linolenic acid (n-3 PUFA) adversely affects early stage of human neuronal differentiation and electrophysiological activity of glutamatergic neurons in vitro

Rett and Rett-related disorders: Common mechanisms for shared symptoms?

FOXG1 Dose in Brain Development

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