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Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities

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...

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Autores principales: Madison, Jon M., Zhou, Fen, Nigam, Aparna, Hussain, Ali, Barker, Douglas D., Nehme, Ralda, van der Ven, Karlijn, Hsu, Jenny, Wolf, Pavlina, Fleishman, Morgan, O’Dushlaine, Colm, Rose, Sam, Chambert, Kimberly, Lau, Frank H., Ahfeldt, Tim, Rueckert, Erroll H., Sheridan, Steven D., Fass, Daniel M., Nemesh, James, Mullen, Thomas E., Daheron, Laurence, McCarroll, Steve, Sklar, Pamela, Perlis, Roy H., Haggarty, Stephen J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440839/
https://www.ncbi.nlm.nih.gov/pubmed/25733313
http://dx.doi.org/10.1038/mp.2015.7
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author Madison, Jon M.
Zhou, Fen
Nigam, Aparna
Hussain, Ali
Barker, Douglas D.
Nehme, Ralda
van der Ven, Karlijn
Hsu, Jenny
Wolf, Pavlina
Fleishman, Morgan
O’Dushlaine, Colm
Rose, Sam
Chambert, Kimberly
Lau, Frank H.
Ahfeldt, Tim
Rueckert, Erroll H.
Sheridan, Steven D.
Fass, Daniel M.
Nemesh, James
Mullen, Thomas E.
Daheron, Laurence
McCarroll, Steve
Sklar, Pamela
Perlis, Roy H.
Haggarty, Stephen J.
author_facet Madison, Jon M.
Zhou, Fen
Nigam, Aparna
Hussain, Ali
Barker, Douglas D.
Nehme, Ralda
van der Ven, Karlijn
Hsu, Jenny
Wolf, Pavlina
Fleishman, Morgan
O’Dushlaine, Colm
Rose, Sam
Chambert, Kimberly
Lau, Frank H.
Ahfeldt, Tim
Rueckert, Erroll H.
Sheridan, Steven D.
Fass, Daniel M.
Nemesh, James
Mullen, Thomas E.
Daheron, Laurence
McCarroll, Steve
Sklar, Pamela
Perlis, Roy H.
Haggarty, Stephen J.
author_sort Madison, Jon M.
collection PubMed
description 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.
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spelling pubmed-44408392015-12-01 Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities Madison, Jon M. Zhou, Fen Nigam, Aparna Hussain, Ali Barker, Douglas D. Nehme, Ralda van der Ven, Karlijn Hsu, Jenny Wolf, Pavlina Fleishman, Morgan O’Dushlaine, Colm Rose, Sam Chambert, Kimberly Lau, Frank H. Ahfeldt, Tim Rueckert, Erroll H. Sheridan, Steven D. Fass, Daniel M. Nemesh, James Mullen, Thomas E. Daheron, Laurence McCarroll, Steve Sklar, Pamela Perlis, Roy H. Haggarty, Stephen J. Mol Psychiatry Article 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. 2015-03-03 2015-06 /pmc/articles/PMC4440839/ /pubmed/25733313 http://dx.doi.org/10.1038/mp.2015.7 Text en http://www.nature.com/authors/editorial_policies/license.html#terms Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Madison, Jon M.
Zhou, Fen
Nigam, Aparna
Hussain, Ali
Barker, Douglas D.
Nehme, Ralda
van der Ven, Karlijn
Hsu, Jenny
Wolf, Pavlina
Fleishman, Morgan
O’Dushlaine, Colm
Rose, Sam
Chambert, Kimberly
Lau, Frank H.
Ahfeldt, Tim
Rueckert, Erroll H.
Sheridan, Steven D.
Fass, Daniel M.
Nemesh, James
Mullen, Thomas E.
Daheron, Laurence
McCarroll, Steve
Sklar, Pamela
Perlis, Roy H.
Haggarty, Stephen J.
Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities
title Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities
title_full Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities
title_fullStr Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities
title_full_unstemmed Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities
title_short Characterization of Bipolar Disorder Patient-Specific Induced Pluripotent Stem Cells from a Family Reveals Neurodevelopmental and mRNA Expression Abnormalities
title_sort characterization of bipolar disorder patient-specific induced pluripotent stem cells from a family reveals neurodevelopmental and mrna expression abnormalities
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4440839/
https://www.ncbi.nlm.nih.gov/pubmed/25733313
http://dx.doi.org/10.1038/mp.2015.7
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