Microglia development follows a stepwise program to regulate brain homeostasis

Orit Matcovitch-Natan; Deborah R Winter; Amir Giladi; Aguilar, Stephanie Vargas Aguilar; Amit Spinrad; Sandrine Sarrazin; Hila Ben-Yehuda; Eyal David; Gonzalez, Fabiola Zelada Gonzalez; Pierre Perrin; Hadas Keren-Shaul; Meital Gury; David Lara-Astaiso; Christoph Alexander Thaiss; Merav Cohen; Halpern, Keren Bahar Halpern; Kuti Baruch; Aleksandra Deczkowska; Vivas, Erika Lorenzo Vivas; Shalev Itzkovitz; Eran Elinav; Michael H Sieweke; Michal Schwartz; Ido Amit

doi:10.1126/science.aad8670

Microglia development follows a stepwise program to regulate brain homeostasis

Orit Matcovitch-Natan, Deborah R Winter, Amir Giladi, Aguilar, Stephanie Vargas Aguilar, Amit Spinrad, Sandrine Sarrazin, Hila Ben-Yehuda, Eyal David, Gonzalez, Fabiola Zelada Gonzalez, Pierre Perrin, Hadas Keren-Shaul, Meital Gury, David Lara-Astaiso, Christoph Alexander Thaiss, Merav Cohen, Halpern, Keren Bahar Halpern, Kuti Baruch, Aleksandra Deczkowska, Vivas, Erika Lorenzo Vivas, Shalev ItzkovitzEran Elinav, Michael H Sieweke, Michal Schwartz, Ido Amit

Weizmann Institute of Science

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

Abstract

Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain-early, pre-, and adult microglia-which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

Original language	English
Article number	aad8670
Journal	Science
Volume	353
Issue number	6301
DOIs	https://doi.org/10.1126/science.aad8670
State	Published - 19 Aug 2016

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Matcovitch-Natan, O., Winter, D. R., Giladi, A., Vargas Aguilar, A. S., Spinrad, A., Sarrazin, S., Ben-Yehuda, H., David, E., Zelada Gonzalez, G. F., Perrin, P., Keren-Shaul, H., Gury, M., Lara-Astaiso, D., Thaiss, C. A., Cohen, M., Bahar Halpern, H. K., Baruch, K., Deczkowska, A., Lorenzo Vivas, V. E., ... Amit, I. (2016). Microglia development follows a stepwise program to regulate brain homeostasis. Science, 353(6301), Article aad8670. https://doi.org/10.1126/science.aad8670

@article{d840086245f744a6b821306870c0c50d,

title = "Microglia development follows a stepwise program to regulate brain homeostasis",

abstract = "Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain-early, pre-, and adult microglia-which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.",

author = "Orit Matcovitch-Natan and Winter, {Deborah R} and Amir Giladi and {Vargas Aguilar}, {Aguilar, Stephanie} and Amit Spinrad and Sandrine Sarrazin and Hila Ben-Yehuda and Eyal David and {Zelada Gonzalez}, {Gonzalez, Fabiola} and Pierre Perrin and Hadas Keren-Shaul and Meital Gury and David Lara-Astaiso and Thaiss, {Christoph Alexander} and Merav Cohen and {Bahar Halpern}, {Halpern, Keren} and Kuti Baruch and Aleksandra Deczkowska and {Lorenzo Vivas}, {Vivas, Erika} and Shalev Itzkovitz and Eran Elinav and Sieweke, {Michael H} and Michal Schwartz and Ido Amit",

note = "Funding Information: We thank members of the I.A. and M.S. laboratories for discussions, T. Wiesel for artwork, M. Barad from the CIML flow cytometry platform for assistance with microglia sorting, and M. Azoulay and O. Rozenberg for animal handling. Research in the I.A. laboratory is supported by the European Research Council (grant 309788); the Israeli Science Foundation (grant 1782/11); the European Commission Seventh Framework Programme (EC FP7) BLUEPRINT consortium; the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; a Minerva Stiftung research grant; the Israeli Ministry of Science, Technology and Space; the David and Fela Shapell Family Foundation; and the National Human Genome Research Institute Center for Excellence in Genome Science (grant 1P50HG006193). I.A. holds the Alan and Laraine Fischer Career Development Chair. Research in the M.S. laboratory is supported by the Advanced European Research Council (grant 232835) and by the EC FP7 HEALTH-2011 program (grant 279017). M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. M.H.S. was supported by grants from the Agence Nationale de la Recherche (grants ANR BLAN07- 1-205752 and ANR-11-BSV3-026-01), the Fondation pour la Recherche M{\'e}dicale (DEq. 20071210559 and DEq. 20110421320), and InCA (French National Cancer Institute; grant 13-10/405/ABLC- HS). M.H.S. is a Berlin Institute of Health Einstein fellow and an INSERM-Helmholtz group leader. D.R.W. is supported by the European Molecular Biology Organization (EMBO; ALT766-2014) and the EC FP7 (Marie Curie Actions, EMBOCOFUND2012, GA-2012-600394). ATAC-seq, ChIP-seq, bulk RNA-seq, and single-cell RNA-seq data are deposited in the Genome Expression Omnibus under accession number GSE79819.",

year = "2016",

month = aug,

day = "19",

doi = "10.1126/science.aad8670",

language = "الإنجليزيّة",

volume = "353",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "6301",

}

Matcovitch-Natan, O, Winter, DR, Giladi, A, Vargas Aguilar, AS, Spinrad, A, Sarrazin, S, Ben-Yehuda, H, David, E, Zelada Gonzalez, GF, Perrin, P, Keren-Shaul, H, Gury, M, Lara-Astaiso, D, Thaiss, CA, Cohen, M, Bahar Halpern, HK, Baruch, K, Deczkowska, A, Lorenzo Vivas, VE, Itzkovitz, S , Elinav, E, Sieweke, MH, Schwartz, M & Amit, I 2016, 'Microglia development follows a stepwise program to regulate brain homeostasis', Science, vol. 353, no. 6301, aad8670. https://doi.org/10.1126/science.aad8670

TY - JOUR

T1 - Microglia development follows a stepwise program to regulate brain homeostasis

AU - Matcovitch-Natan, Orit

AU - Winter, Deborah R

AU - Giladi, Amir

AU - Vargas Aguilar, Aguilar, Stephanie

AU - Spinrad, Amit

AU - Sarrazin, Sandrine

AU - Ben-Yehuda, Hila

AU - David, Eyal

AU - Zelada Gonzalez, Gonzalez, Fabiola

AU - Perrin, Pierre

AU - Keren-Shaul, Hadas

AU - Gury, Meital

AU - Lara-Astaiso, David

AU - Thaiss, Christoph Alexander

AU - Cohen, Merav

AU - Bahar Halpern, Halpern, Keren

AU - Baruch, Kuti

AU - Deczkowska, Aleksandra

AU - Lorenzo Vivas, Vivas, Erika

AU - Itzkovitz, Shalev

AU - Elinav, Eran

AU - Sieweke, Michael H

AU - Schwartz, Michal

AU - Amit, Ido

N1 - Funding Information: We thank members of the I.A. and M.S. laboratories for discussions, T. Wiesel for artwork, M. Barad from the CIML flow cytometry platform for assistance with microglia sorting, and M. Azoulay and O. Rozenberg for animal handling. Research in the I.A. laboratory is supported by the European Research Council (grant 309788); the Israeli Science Foundation (grant 1782/11); the European Commission Seventh Framework Programme (EC FP7) BLUEPRINT consortium; the Ernest and Bonnie Beutler Research Program of Excellence in Genomic Medicine; a Minerva Stiftung research grant; the Israeli Ministry of Science, Technology and Space; the David and Fela Shapell Family Foundation; and the National Human Genome Research Institute Center for Excellence in Genome Science (grant 1P50HG006193). I.A. holds the Alan and Laraine Fischer Career Development Chair. Research in the M.S. laboratory is supported by the Advanced European Research Council (grant 232835) and by the EC FP7 HEALTH-2011 program (grant 279017). M.S. holds the Maurice and Ilse Katz Professorial Chair in Neuroimmunology. M.H.S. was supported by grants from the Agence Nationale de la Recherche (grants ANR BLAN07- 1-205752 and ANR-11-BSV3-026-01), the Fondation pour la Recherche Médicale (DEq. 20071210559 and DEq. 20110421320), and InCA (French National Cancer Institute; grant 13-10/405/ABLC- HS). M.H.S. is a Berlin Institute of Health Einstein fellow and an INSERM-Helmholtz group leader. D.R.W. is supported by the European Molecular Biology Organization (EMBO; ALT766-2014) and the EC FP7 (Marie Curie Actions, EMBOCOFUND2012, GA-2012-600394). ATAC-seq, ChIP-seq, bulk RNA-seq, and single-cell RNA-seq data are deposited in the Genome Expression Omnibus under accession number GSE79819.

PY - 2016/8/19

Y1 - 2016/8/19

N2 - Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain-early, pre-, and adult microglia-which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

AB - Microglia, the resident myeloid cells of the central nervous system, play important roles in life-long brain maintenance and in pathology. Despite their importance, their regulatory dynamics during brain development have not been fully elucidated. Using genome-wide chromatin and expression profiling coupled with single-cell transcriptomic analysis throughout development, we found that microglia undergo three temporal stages of development in synchrony with the brain-early, pre-, and adult microglia-which are under distinct regulatory circuits. Knockout of the gene encoding the adult microglia transcription factor MAFB and environmental perturbations, such as those affecting the microbiome or prenatal immune activation, led to disruption of developmental genes and immune response pathways. Together, our work identifies a stepwise microglia developmental program integrating immune response pathways that may be associated with several neurodevelopmental disorders.

UR - http://www.scopus.com/inward/record.url?scp=84976883162&partnerID=8YFLogxK

U2 - 10.1126/science.aad8670

DO - 10.1126/science.aad8670

M3 - مقالة

C2 - 27338705

SN - 0036-8075

VL - 353

JO - Science

JF - Science

IS - 6301

M1 - aad8670

ER -

Microglia development follows a stepwise program to regulate brain homeostasis

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