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Induced Pluripotent Stem Cells Reveal Common Neurodevelopmental Genome Deprograming in Schizophrenia
Sridhar T Narla1, Brandon Decker1, Pinaki Sarder1,2
1Department of Pathology and Anatomical Sciences, Molecular and Structural Neurobiology and Gene Therapy Program, State University of New York, Buffalo, NY, USA.
Results and Problems in Cell Differentiation
|September 14, 2018
Summary
Schizophrenia stems from early brain developmental genomic changes, not just genetics. Diverse gene mutations converge on a common pathway, integrative nuclear (n)FGFR1 signaling, causing widespread gene network dysregulation.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Schizophrenia is a complex neurodevelopmental disorder with genetic links.
- Its origins are established during prenatal development, preceding clinical symptoms.
- Over 200 genes are associated with schizophrenia, but the convergence mechanism is unclear.
Purpose of the Study:
- To investigate the common neurodevelopmental pathway affected by schizophrenia-linked genes.
- To explore the role of integrative nuclear (n)FGFR1 signaling (INFS) in schizophrenia etiology.
- To determine if dysregulated gene networks are shared across genetically distinct schizophrenia cases.
Main Methods:
- Utilized induced pluripotent stem cell (iPSC) and embryonic stem cell (ESC)-derived neuronal committed cells (NCCs).
- Conducted a multi-channeled investigation of gene expression and signaling pathways.
- Analyzed nFGFR1-genome interactions and miRNA gene regulation.
Main Results:
- Identified an early, pre-neuronal developmental-genomic etiology for schizophrenia.
- Found common dysregulated developmental gene networks in genetically unrelated schizophrenia cases.
- Demonstrated that INFS dysregulation deconstructs and reforms gene networks in schizophrenia NCCs.
Conclusions:
- Schizophrenia arises from a "watershed" mechanism where diverse mutations impact the INFS pathway.
- Altered nFGFR1-genome interactions and miRNA deregulation contribute to genomic deprogramming.
- Chromatin topology changes mediated by nFGFR1 may drive coordinated gene dysregulation in schizophrenia.
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