A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages

Simone Brioschi; Julia A. Belk; Vincent Peng; Martina Molgora; Patrick Fernandes Rodrigues; Khai M. Nguyen; Shoutang Wang; Siling Du; Wei Le Wang; Gary E. Grajales-Reyes; Jennifer M. Ponce; Carla M. Yuede; Qingyun Li; John M. Baer; David G. DeNardo; Susan Gilfillan; Marina Cella; Ansuman T. Satpathy; Marco Colonna

doi:10.1016/j.immuni.2023.01.028

A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages

Simone Brioschi, Julia A. Belk, Vincent Peng, Martina Molgora, Patrick Fernandes Rodrigues, Khai M. Nguyen, Shoutang Wang, Siling Du, Wei Le Wang, Gary E. Grajales-Reyes, Jennifer M. Ponce, Carla M. Yuede, Qingyun Li, John M. Baer, David G. DeNardo, Susan Gilfillan, Marina Cella, Ansuman T. Satpathy, Marco Colonna

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

30 Scopus citations

Abstract

Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.

Original language	English
Pages (from-to)	1027-1045.e8
Journal	Immunity
Volume	56
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2023.01.028
State	Published - May 9 2023

Keywords

BAMs
SMAD4
fate-mapping
macrophages ontogeny
microglia

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10.1016/j.immuni.2023.01.028

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Brioschi, S., Belk, J. A., Peng, V., Molgora, M., Rodrigues, P. F., Nguyen, K. M., Wang, S., Du, S., Wang, W. L., Grajales-Reyes, G. E., Ponce, J. M., Yuede, C. M., Li, Q., Baer, J. M., DeNardo, D. G., Gilfillan, S., Cella, M., Satpathy, A. T., & Colonna, M. (2023). A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages. Immunity, 56(5), 1027-1045.e8. https://doi.org/10.1016/j.immuni.2023.01.028

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title = "A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages",

abstract = "Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.",

keywords = "BAMs, SMAD4, fate-mapping, macrophages ontogeny, microglia",

author = "Simone Brioschi and Belk, {Julia A.} and Vincent Peng and Martina Molgora and Rodrigues, {Patrick Fernandes} and Nguyen, {Khai M.} and Shoutang Wang and Siling Du and Wang, {Wei Le} and Grajales-Reyes, {Gary E.} and Ponce, {Jennifer M.} and Yuede, {Carla M.} and Qingyun Li and Baer, {John M.} and DeNardo, {David G.} and Susan Gilfillan and Marina Cella and Satpathy, {Ansuman T.} and Marco Colonna",

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year = "2023",

month = may,

day = "9",

doi = "10.1016/j.immuni.2023.01.028",

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Brioschi, S, Belk, JA, Peng, V, Molgora, M, Rodrigues, PF, Nguyen, KM, Wang, S, Du, S, Wang, WL, Grajales-Reyes, GE, Ponce, JM, Yuede, CM , Li, Q, Baer, JM, DeNardo, DG , Gilfillan, S , Cella, M, Satpathy, AT & Colonna, M 2023, 'A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages', Immunity, vol. 56, no. 5, pp. 1027-1045.e8. https://doi.org/10.1016/j.immuni.2023.01.028

TY - JOUR

T1 - A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages

AU - Brioschi, Simone

AU - Belk, Julia A.

AU - Peng, Vincent

AU - Molgora, Martina

AU - Rodrigues, Patrick Fernandes

AU - Nguyen, Khai M.

AU - Wang, Shoutang

AU - Du, Siling

AU - Wang, Wei Le

AU - Grajales-Reyes, Gary E.

AU - Ponce, Jennifer M.

AU - Yuede, Carla M.

AU - Li, Qingyun

AU - Baer, John M.

AU - DeNardo, David G.

AU - Gilfillan, Susan

AU - Cella, Marina

AU - Satpathy, Ansuman T.

AU - Colonna, Marco

PY - 2023/5/9

Y1 - 2023/5/9

N2 - Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.

AB - Genetic tools to target microglia specifically and efficiently from the early stages of embryonic development are lacking. We generated a constitutive Cre line controlled by the microglia signature gene Crybb1 that produced nearly complete recombination in embryonic brain macrophages (microglia and border-associated macrophages [BAMs]) by the perinatal period, with limited recombination in peripheral myeloid cells. Using this tool in combination with Flt3-Cre lineage tracer, single-cell RNA-sequencing analysis, and confocal imaging, we resolved embryonic-derived versus monocyte-derived BAMs in the mouse cortex. Deletion of the transcription factor SMAD4 in microglia and embryonic-derived BAMs using Crybb1-Cre caused a developmental arrest of microglia, which instead acquired a BAM specification signature. By contrast, the development of genuine BAMs remained unaffected. Our results reveal that SMAD4 drives a transcriptional and epigenetic program that is indispensable for the commitment of brain macrophages to the microglia fate and highlight Crybb1-Cre as a tool for targeting embryonic brain macrophages.

KW - BAMs

KW - SMAD4

KW - fate-mapping

KW - macrophages ontogeny

KW - microglia

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U2 - 10.1016/j.immuni.2023.01.028

DO - 10.1016/j.immuni.2023.01.028

M3 - Article

C2 - 36791722

AN - SCOPUS:85149918726

SN - 1074-7613

VL - 56

SP - 1027-1045.e8

JO - Immunity

JF - Immunity

IS - 5

ER -

A Cre-deleter specific for embryo-derived brain macrophages reveals distinct features of microglia and border macrophages

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Keywords

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