Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities
| العنوان: | Characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mRNA expression abnormalities |
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| المؤلفون: | Frank H. Lau, Pamela Sklar, Stephen J. Haggarty, Samuel A. Rose, Roy H. Perlis, Steven D. Sheridan, Steven A. McCarroll, James Nemesh, Philip A. Wolf, Colm O'Dushlaine, A Hussain, Ralda Nehme, A Nigam, E H Rueckert, Douglas Barker, Daniel M. Fass, M Fleishman, Joey Hsu, Jon M. Madison, Fen Zhou, K van der Ven, Kimberly Chambert, Thomas E. Mullen, Tim Ahfeldt, Laurence Daheron |
| المصدر: | Molecular psychiatry |
| بيانات النشر: | Springer Science and Business Media LLC, 2015. |
| سنة النشر: | 2015 |
| مصطلحات موضوعية: | Male, Bipolar Disorder, Cellular differentiation, Gene Expression, GSK3, Membrane Potentials, Glycogen Synthase Kinase 3, 0302 clinical medicine, GSK-3, calcium channels, Gene expression, Induced pluripotent stem cell, Wnt Signaling Pathway, Cells, Cultured, Neurons, 0303 health sciences, iPSC, neurodevelopment, Wnt signaling pathway, ion channels, Cell Differentiation, 3. Good health, Psychiatry and Mental health, lithium, Schizophrenia, Cytokines, Intercellular Signaling Peptides and Proteins, Female, Stem cell, Receptors, CXCR4, DNA Copy Number Variations, neuroplasticity, Induced Pluripotent Stem Cells, Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, mental disorders, medicine, Humans, RNA, Messenger, Bipolar disorder, Molecular Biology, 030304 developmental biology, Family Health, medicine.disease, stem cell, Cancer research, Neuroscience, 030217 neurology & neurosurgery, corticogenesis, Transcription Factors |
| الوصف: | Bipolar disorder (BD) is a common neuropsychiatric disorder characterized by chronic recurrent episodes of depression and mania. Despite evidence for high heritability of BD, little is known about its underlying pathophysiology. To develop new tools for investigating the molecular and cellular basis of BD we applied a family-based paradigm to derive and characterize a set of 12 induced pluripotent stem cell (iPSC) lines from a quartet consisting of two BD-affected brothers and their two unaffected parents. Initially, no significant phenotypic differences were observed between iPSCs derived from the different family members. However, upon directed neural differentiation we observed that CXCR4 (CXC chemokine receptor-4) expressing central nervous system (CNS) neural progenitor cells (NPCs) from both BD patients compared to their unaffected parents exhibited multiple phenotypic differences at the level of neurogenesis and expression of genes critical for neuroplasticity, including WNT pathway components and ion channel subunits. Treatment of the CXCR4+ NPCs with a pharmacological inhibitor of glycogen synthase kinase 3 (GSK3), a known regulator of WNT signaling, was found to rescue a progenitor proliferation deficit in the BD-patient NPCs. Taken together, these studies provide new cellular tools for dissecting the pathophysiology of BD and evidence for dysregulation of key pathways involved in neurodevelopment and neuroplasticity. Future generation of additional iPSCs following a family-based paradigm for modeling complex neuropsychiatric disorders in conjunction with in-depth phenotyping holds promise for providing insights into the pathophysiological substrates of BD and is likely to inform the development of targeted therapeutics for its treatment and ideally prevention. |
| تدمد: | 1476-5578 1359-4184 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::f2e70a47203546670792b54e2189d726Test https://doi.org/10.1038/mp.2015.7Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....f2e70a47203546670792b54e2189d726 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 14765578 13594184 |
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