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Investigating prenatal stress in a stem cell model of human neuronal development
Investigating prenatal stress in a stem cell model of human neuronal development
Prenatal stress is a known risk factor for alterations in brain structure, cognition and behavior associated with neurodevelopmental psychiatric disorders. However, underlying molecular mechanisms are not fully understood and have never been investigated in live human embryonic neuronal cells. This study aimed at examining the potential molecular effects of prenatal stress on the developing brain by modelling embryonic neurogenesis in human stem cells and inducing glucocorticoid receptor-dependent epigenetic changes. Embryonic stem cells and induced pluripotent stem cells were differentiated into ventricular zone-like neuronal progenitors and migrating neurons. Glucocorticoid receptor expression and translocation to the nucleus upon stimulation with dexamethasone were traced across neuronal development and epigenomic changes assessed by alterations in methylation profile and differential gene expression. The results support an intrinsic role of the glucocorticoid receptor during early neurogenesis and suggest that exposure to external glucocorticoids has little effect on neurulating cells up until the start of radial migration towards outer cortical layers. In migrating neurons however, glucocorticoid receptor activation led to hypermethylation of genes with well-established implications in psychiatric disorders, forebrain development, migration, axon development, and Wnt signaling. These effects were mirrored on the transcriptome level in that the number of genes significantly regulated by dexamethasone exposure increased in parallel with glucocorticoid receptor expression and translocation to the nucleus over neural differentiation. An understanding of the molecular mechanisms linking prenatal stress to psychiatric disorders may both help promote awareness of its impact and the development of targeted interventions.
prenatal stress, mental health, psychiatric disorders, neurodevelopmental disorders, schizophrenia, autism, stem cells, induced pluripotent stem cells, DNA methylation, RNA-Seq, GR, Glucocorticoid Receptor
Papst, Lilia
2019
English
Universitätsbibliothek der Ludwig-Maximilians-Universität München
Papst, Lilia (2019): Investigating prenatal stress in a stem cell model of human neuronal development. Dissertation, LMU München: Graduate School of Systemic Neurosciences (GSN)
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Abstract

Prenatal stress is a known risk factor for alterations in brain structure, cognition and behavior associated with neurodevelopmental psychiatric disorders. However, underlying molecular mechanisms are not fully understood and have never been investigated in live human embryonic neuronal cells. This study aimed at examining the potential molecular effects of prenatal stress on the developing brain by modelling embryonic neurogenesis in human stem cells and inducing glucocorticoid receptor-dependent epigenetic changes. Embryonic stem cells and induced pluripotent stem cells were differentiated into ventricular zone-like neuronal progenitors and migrating neurons. Glucocorticoid receptor expression and translocation to the nucleus upon stimulation with dexamethasone were traced across neuronal development and epigenomic changes assessed by alterations in methylation profile and differential gene expression. The results support an intrinsic role of the glucocorticoid receptor during early neurogenesis and suggest that exposure to external glucocorticoids has little effect on neurulating cells up until the start of radial migration towards outer cortical layers. In migrating neurons however, glucocorticoid receptor activation led to hypermethylation of genes with well-established implications in psychiatric disorders, forebrain development, migration, axon development, and Wnt signaling. These effects were mirrored on the transcriptome level in that the number of genes significantly regulated by dexamethasone exposure increased in parallel with glucocorticoid receptor expression and translocation to the nucleus over neural differentiation. An understanding of the molecular mechanisms linking prenatal stress to psychiatric disorders may both help promote awareness of its impact and the development of targeted interventions.