Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity

Ki Jun Yoon; Ha Nam Nguyen; Gianluca Ursini; Fengyu Zhang; Nam Shik Kim; Zhexing Wen; Georgia Makri; David Nauen; Joo Heon Shin; Youngbin Park; Raeeun Chung; Eva Pekle; Ce Zhang; Maxwell Towe; Syed Mohammed Qasim Hussaini; Yohan Lee; Dan Rujescu; David St. Clair; Joel E. Kleinman; Thomas M. Hyde; Gregory Krauss; Kimberly M. Christian; Judith L. Rapoport; Daniel R. Weinberger; Hongjun Song; Guo Li Ming

doi:10.1016/j.stem.2014.05.003

Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity

Ki Jun Yoon, Ha Nam Nguyen, Gianluca Ursini, Fengyu Zhang, Nam Shik Kim, Zhexing Wen, Georgia Makri, David Nauen, Joo Heon Shin, Youngbin Park, Raeeun Chung, Eva Pekle, Ce Zhang, Maxwell Towe, Syed Mohammed Qasim Hussaini, Yohan Lee, Dan Rujescu, David St. Clair, Joel E. Kleinman, Thomas M. HydeGregory Krauss, Kimberly M. Christian, Judith L. Rapoport, Daniel R. Weinberger, Hongjun Song^*, Guo Li Ming

^*Corresponding author for this work

Applied Medicine

Research output: Contribution to journal › Article › peer-review

201 Citations (Scopus)

Abstract

Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

Original language	English
Pages (from-to)	79-91
Number of pages	13
Journal	Cell Stem Cell
Volume	15
Issue number	1
Early online date	3 Jul 2014
DOIs	https://doi.org/10.1016/j.stem.2014.05.003
Publication status	Published - 3 Jul 2014

Bibliographical note

We would like to thank members of G.-l.M. and H.S. laboratories for discussion, ICE stem cell core and H. Kim for generating some iPSC lines, K. Ahn, T. Andersen, V. Villagomez, L. Liu, and Y. Cai for technical support and help. This work was supported by NIH (NS048271, HD069184), the Brain and Behavior Research Foundation (NARSAD), and the Maryland Stem Cell Research Fund (MSCRF) (to G.-l.M.), the Simons Foundation Autism Research Initiative (SFARI), NIH (NS047344, MH087874), and the International Mental Health Research Organization (IMHRO) to H.S., the Lieber Institute for Brain Development to D.R.W., J.E.K., and T.M.H., NARSAD and MSCRF to K.M.C., by fellowships from HFSP to K-j.Y. and MSCRF to G.M., N.-S.K., and Z.W., and from NIH (F31MH102978) to H.N.N.

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Yoon, K. J., Nguyen, H. N., Ursini, G., Zhang, F., Kim, N. S., Wen, Z., Makri, G., Nauen, D., Shin, J. H., Park, Y., Chung, R., Pekle, E., Zhang, C., Towe, M., Hussaini, S. M. Q., Lee, Y., Rujescu, D., St. Clair, D., Kleinman, J. E., ... Ming, G. L. (2014). Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity. Cell Stem Cell, 15(1), 79-91. https://doi.org/10.1016/j.stem.2014.05.003

Yoon, KJ, Nguyen, HN, Ursini, G, Zhang, F, Kim, NS, Wen, Z, Makri, G, Nauen, D, Shin, JH, Park, Y, Chung, R, Pekle, E, Zhang, C, Towe, M, Hussaini, SMQ, Lee, Y, Rujescu, D, St. Clair, D, Kleinman, JE, Hyde, TM, Krauss, G, Christian, KM, Rapoport, JL, Weinberger, DR, Song, H & Ming, GL 2014, 'Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity', Cell Stem Cell, vol. 15, no. 1, pp. 79-91. https://doi.org/10.1016/j.stem.2014.05.003

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title = "Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity",

abstract = "Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.",

author = "Yoon, {Ki Jun} and Nguyen, {Ha Nam} and Gianluca Ursini and Fengyu Zhang and Kim, {Nam Shik} and Zhexing Wen and Georgia Makri and David Nauen and Shin, {Joo Heon} and Youngbin Park and Raeeun Chung and Eva Pekle and Ce Zhang and Maxwell Towe and Hussaini, {Syed Mohammed Qasim} and Yohan Lee and Dan Rujescu and {St. Clair}, David and Kleinman, {Joel E.} and Hyde, {Thomas M.} and Gregory Krauss and Christian, {Kimberly M.} and Rapoport, {Judith L.} and Weinberger, {Daniel R.} and Hongjun Song and Ming, {Guo Li}",

note = "We would like to thank members of G.-l.M. and H.S. laboratories for discussion, ICE stem cell core and H. Kim for generating some iPSC lines, K. Ahn, T. Andersen, V. Villagomez, L. Liu, and Y. Cai for technical support and help. This work was supported by NIH (NS048271, HD069184), the Brain and Behavior Research Foundation (NARSAD), and the Maryland Stem Cell Research Fund (MSCRF) (to G.-l.M.), the Simons Foundation Autism Research Initiative (SFARI), NIH (NS047344, MH087874), and the International Mental Health Research Organization (IMHRO) to H.S., the Lieber Institute for Brain Development to D.R.W., J.E.K., and T.M.H., NARSAD and MSCRF to K.M.C., by fellowships from HFSP to K-j.Y. and MSCRF to G.M., N.-S.K., and Z.W., and from NIH (F31MH102978) to H.N.N.",

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doi = "10.1016/j.stem.2014.05.003",

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T1 - Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity

AU - Yoon, Ki Jun

AU - Nguyen, Ha Nam

AU - Ursini, Gianluca

AU - Zhang, Fengyu

AU - Kim, Nam Shik

AU - Wen, Zhexing

AU - Makri, Georgia

AU - Nauen, David

AU - Shin, Joo Heon

AU - Park, Youngbin

AU - Chung, Raeeun

AU - Pekle, Eva

AU - Zhang, Ce

AU - Towe, Maxwell

AU - Hussaini, Syed Mohammed Qasim

AU - Lee, Yohan

AU - Rujescu, Dan

AU - St. Clair, David

AU - Kleinman, Joel E.

AU - Hyde, Thomas M.

AU - Krauss, Gregory

AU - Christian, Kimberly M.

AU - Rapoport, Judith L.

AU - Weinberger, Daniel R.

AU - Song, Hongjun

AU - Ming, Guo Li

N1 - We would like to thank members of G.-l.M. and H.S. laboratories for discussion, ICE stem cell core and H. Kim for generating some iPSC lines, K. Ahn, T. Andersen, V. Villagomez, L. Liu, and Y. Cai for technical support and help. This work was supported by NIH (NS048271, HD069184), the Brain and Behavior Research Foundation (NARSAD), and the Maryland Stem Cell Research Fund (MSCRF) (to G.-l.M.), the Simons Foundation Autism Research Initiative (SFARI), NIH (NS047344, MH087874), and the International Mental Health Research Organization (IMHRO) to H.S., the Lieber Institute for Brain Development to D.R.W., J.E.K., and T.M.H., NARSAD and MSCRF to K.M.C., by fellowships from HFSP to K-j.Y. and MSCRF to G.M., N.-S.K., and Z.W., and from NIH (F31MH102978) to H.N.N.

PY - 2014/7/3

Y1 - 2014/7/3

N2 - Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

AB - Defects in brain development are believed to contribute toward the onset of neuropsychiatric disorders, but identifying specific underlying mechanisms has proven difficult. Here, we took a multifaceted approach to investigate why 15q11.2 copy number variants are prominent risk factors for schizophrenia and autism. First, we show that human iPSC-derived neural progenitors carrying 15q11.2 microdeletion exhibit deficits in adherens junctions and apical polarity. This results from haploinsufficiency of CYFIP1, a gene within 15q11.2 that encodes a subunit of the WAVE complex, which regulates cytoskeletal dynamics. In developing mouse cortex, deficiency in CYFIP1 and WAVE signaling similarly affects radial glial cells, leading to their ectopic localization outside of the ventricular zone. Finally, targeted human genetic association analyses revealed an epistatic interaction between CYFIP1 and WAVE signaling mediator ACTR2 and risk for schizophrenia. Our findings provide insight into how CYFIP1 regulates neural stem cell function and may contribute to the susceptibility of neuropsychiatric disorders.

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Modeling a genetic risk for schizophrenia in iPSCs and Mice reveals neural stem cell deficits associated with adherens junctions and polarity

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Bibliographical note

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