Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia

Eunchai Kang; Katherine E Burdick; Ju Young Kim; Xin Duan; Junjie U Guo; Kurt A Sailor; Dhong-Eun Jung; Sundar Ganesan; Sungkyung Choi; Dennis Pradhan; Bai Lu; Dimitrios Avramopoulos; Kimberly Christian; Anil K Malhotra; Hongjun Song; Guo-li Ming

doi:10.1016/j.neuron.2011.09.032

Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia

Eunchai Kang, Katherine E Burdick, Ju Young Kim, Xin Duan, Junjie U Guo, Kurt A Sailor, Dhong-Eun Jung, Sundar Ganesan, Sungkyung Choi, Dennis Pradhan, Bai Lu, Dimitrios Avramopoulos, Kimberly Christian, Anil K Malhotra, Hongjun Song, Guo-li Ming

Johns Hopkins University

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

76 Citations (Scopus)

Abstract

Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.

Original language	English
Pages (from-to)	559-71
Number of pages	13
Journal	Neuron
Volume	72
Issue number	4
Early online date	16 Nov 2011
DOIs	https://doi.org/10.1016/j.neuron.2011.09.032
Publication status	Published - 16 Nov 2011
Externally published	Yes

Bibliographical note

Copyright © 2011 Elsevier Inc. All rights reserved.

Acknowledgements: We thank D. Weinberg, D. Valle, and members of Ming and Song Laboratories for critical comments, L. Liu, Y. Cai, and H. Qasim for technical support, and A. Sawa and A. Kamiya for anti-NDEL1 antibodies. This work was supported by NIH (NS048271, HD069184), NARSAD, and MSCRF to G.-l.M., by NIH (NS047344, AG024984, MH084018, MH087874), IMHRO and Johns Hopkins BSI to H.S., by MH79800, MH080173 and the Donald and Barbara Zucker Foundation to A.K.M., and by MH077807 to K.E.B., J.Y.K., and K.C. were partially supported by postdoctoral fellowships from MSCRF.

Keywords

Adaptor Proteins, Signal Transducing/deficiency
Adult
Aged
Animals
Case-Control Studies
Cells, Cultured
Female
Gene Knockdown Techniques
Genetic Association Studies
Hippocampus/growth & development
Humans
Male
Mice
Mice, Inbred C57BL
Middle Aged
Nerve Tissue Proteins/deficiency
Neurogenesis/genetics
Polymorphism, Single Nucleotide/genetics
Protein Binding/genetics
Risk Factors
Schizophrenia/genetics

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Kang, E., Burdick, K. E., Kim, J. Y., Duan, X., Guo, J. U., Sailor, K. A., Jung, D.-E., Ganesan, S., Choi, S., Pradhan, D., Lu, B., Avramopoulos, D., Christian, K., Malhotra, A. K., Song, H., & Ming, G. (2011). Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia. Neuron, 72(4), 559-71. https://doi.org/10.1016/j.neuron.2011.09.032

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title = "Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia",

abstract = "Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.",

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author = "Eunchai Kang and Burdick, {Katherine E} and Kim, {Ju Young} and Xin Duan and Guo, {Junjie U} and Sailor, {Kurt A} and Dhong-Eun Jung and Sundar Ganesan and Sungkyung Choi and Dennis Pradhan and Bai Lu and Dimitrios Avramopoulos and Kimberly Christian and Malhotra, {Anil K} and Hongjun Song and Guo-li Ming",

note = "Copyright {\textcopyright} 2011 Elsevier Inc. All rights reserved. Acknowledgements: We thank D. Weinberg, D. Valle, and members of Ming and Song Laboratories for critical comments, L. Liu, Y. Cai, and H. Qasim for technical support, and A. Sawa and A. Kamiya for anti-NDEL1 antibodies. This work was supported by NIH (NS048271, HD069184), NARSAD, and MSCRF to G.-l.M., by NIH (NS047344, AG024984, MH084018, MH087874), IMHRO and Johns Hopkins BSI to H.S., by MH79800, MH080173 and the Donald and Barbara Zucker Foundation to A.K.M., and by MH077807 to K.E.B., J.Y.K., and K.C. were partially supported by postdoctoral fellowships from MSCRF.",

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AU - Kang, Eunchai

AU - Burdick, Katherine E

AU - Kim, Ju Young

AU - Duan, Xin

AU - Guo, Junjie U

AU - Sailor, Kurt A

AU - Jung, Dhong-Eun

AU - Ganesan, Sundar

AU - Choi, Sungkyung

AU - Pradhan, Dennis

AU - Lu, Bai

AU - Avramopoulos, Dimitrios

AU - Christian, Kimberly

AU - Malhotra, Anil K

AU - Song, Hongjun

AU - Ming, Guo-li

N1 - Copyright © 2011 Elsevier Inc. All rights reserved. Acknowledgements: We thank D. Weinberg, D. Valle, and members of Ming and Song Laboratories for critical comments, L. Liu, Y. Cai, and H. Qasim for technical support, and A. Sawa and A. Kamiya for anti-NDEL1 antibodies. This work was supported by NIH (NS048271, HD069184), NARSAD, and MSCRF to G.-l.M., by NIH (NS047344, AG024984, MH084018, MH087874), IMHRO and Johns Hopkins BSI to H.S., by MH79800, MH080173 and the Donald and Barbara Zucker Foundation to A.K.M., and by MH077807 to K.E.B., J.Y.K., and K.C. were partially supported by postdoctoral fellowships from MSCRF.

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N2 - Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.

AB - Disrupted-in Schizophrenia 1 (DISC1), a susceptibility gene for major mental disorders, encodes a scaffold protein that has a multifaceted impact on neuronal development. How DISC1 regulates different aspects of neuronal development is not well understood. Here, we show that Fasciculation and Elongation Protein Zeta-1 (FEZ1) interacts with DISC1 to synergistically regulate dendritic growth of newborn neurons in the adult mouse hippocampus, and that this pathway complements a parallel DISC1-NDEL1 interaction that regulates cell positioning and morphogenesis of newborn neurons. Furthermore, genetic association analysis of two independent cohorts of schizophrenia patients and healthy controls reveals an epistatic interaction between FEZ1 and DISC1, but not between FEZ1 and NDEL1, for risk of schizophrenia. Our findings support a model in which DISC1 regulates distinct aspects of neuronal development through its interaction with different intracellular partners and such epistasis may contribute to increased risk for schizophrenia.

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KW - Aged

KW - Animals

KW - Case-Control Studies

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KW - Female

KW - Gene Knockdown Techniques

KW - Genetic Association Studies

KW - Hippocampus/growth & development

KW - Humans

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Nerve Tissue Proteins/deficiency

KW - Neurogenesis/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Protein Binding/genetics

KW - Risk Factors

KW - Schizophrenia/genetics

U2 - 10.1016/j.neuron.2011.09.032

DO - 10.1016/j.neuron.2011.09.032

M3 - Article

C2 - 22099459

SN - 0896-6273

VL - 72

SP - 559

EP - 571

JO - Neuron

JF - Neuron

IS - 4

ER -

Interaction between FEZ1 and DISC1 in regulation of neuronal development and risk for schizophrenia

Abstract

Bibliographical note

Keywords

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