Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased prote...
Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Logiacco, Francesca [verfasserIn] Grzegorzek, Laura Cathleen Cordell, Elizabeth C. Popp, Oliver Mertins, Philipp Gutmann, David H. Kettenmann, Helmut Semtner, Marcus

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2023

Schlagwörter:	Neurofibromin NF1 Purinergic signaling Sex differences Microglia Cortex Genetically engineered mice

Anmerkung:	© The Author(s) 2023

Übergeordnetes Werk:	Enthalten in: Acta Neuropathologica Communications - London : Biomed Central, 2013, 11(2023), 1 vom: 09. März
Übergeordnetes Werk:	volume:11 ; year:2023 ; number:1 ; day:09 ; month:03

Links:	Volltext

DOI / URN:	10.1186/s40478-023-01525-w

Katalog-ID:	SPR049609114

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520			\|a Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells.
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allfields	10.1186/s40478-023-01525-w doi (DE-627)SPR049609114 (SPR)s40478-023-01525-w-e DE-627 ger DE-627 rakwb eng Logiacco, Francesca verfasserin aut Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. Neurofibromin (dpeaa)DE-He213 NF1 (dpeaa)DE-He213 Purinergic signaling (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Cortex (dpeaa)DE-He213 Genetically engineered mice (dpeaa)DE-He213 Grzegorzek, Laura Cathleen aut Cordell, Elizabeth C. aut Popp, Oliver aut Mertins, Philipp aut Gutmann, David H. aut Kettenmann, Helmut aut Semtner, Marcus aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 09. März (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:09 month:03 https://dx.doi.org/10.1186/s40478-023-01525-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 09 03
spelling	10.1186/s40478-023-01525-w doi (DE-627)SPR049609114 (SPR)s40478-023-01525-w-e DE-627 ger DE-627 rakwb eng Logiacco, Francesca verfasserin aut Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. Neurofibromin (dpeaa)DE-He213 NF1 (dpeaa)DE-He213 Purinergic signaling (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Cortex (dpeaa)DE-He213 Genetically engineered mice (dpeaa)DE-He213 Grzegorzek, Laura Cathleen aut Cordell, Elizabeth C. aut Popp, Oliver aut Mertins, Philipp aut Gutmann, David H. aut Kettenmann, Helmut aut Semtner, Marcus aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 09. März (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:09 month:03 https://dx.doi.org/10.1186/s40478-023-01525-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 09 03
allfields_unstemmed	10.1186/s40478-023-01525-w doi (DE-627)SPR049609114 (SPR)s40478-023-01525-w-e DE-627 ger DE-627 rakwb eng Logiacco, Francesca verfasserin aut Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. Neurofibromin (dpeaa)DE-He213 NF1 (dpeaa)DE-He213 Purinergic signaling (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Cortex (dpeaa)DE-He213 Genetically engineered mice (dpeaa)DE-He213 Grzegorzek, Laura Cathleen aut Cordell, Elizabeth C. aut Popp, Oliver aut Mertins, Philipp aut Gutmann, David H. aut Kettenmann, Helmut aut Semtner, Marcus aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 09. März (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:09 month:03 https://dx.doi.org/10.1186/s40478-023-01525-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 09 03
allfieldsGer	10.1186/s40478-023-01525-w doi (DE-627)SPR049609114 (SPR)s40478-023-01525-w-e DE-627 ger DE-627 rakwb eng Logiacco, Francesca verfasserin aut Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. Neurofibromin (dpeaa)DE-He213 NF1 (dpeaa)DE-He213 Purinergic signaling (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Cortex (dpeaa)DE-He213 Genetically engineered mice (dpeaa)DE-He213 Grzegorzek, Laura Cathleen aut Cordell, Elizabeth C. aut Popp, Oliver aut Mertins, Philipp aut Gutmann, David H. aut Kettenmann, Helmut aut Semtner, Marcus aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 09. März (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:09 month:03 https://dx.doi.org/10.1186/s40478-023-01525-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 09 03
allfieldsSound	10.1186/s40478-023-01525-w doi (DE-627)SPR049609114 (SPR)s40478-023-01525-w-e DE-627 ger DE-627 rakwb eng Logiacco, Francesca verfasserin aut Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic 2023 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s) 2023 Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. Neurofibromin (dpeaa)DE-He213 NF1 (dpeaa)DE-He213 Purinergic signaling (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Cortex (dpeaa)DE-He213 Genetically engineered mice (dpeaa)DE-He213 Grzegorzek, Laura Cathleen aut Cordell, Elizabeth C. aut Popp, Oliver aut Mertins, Philipp aut Gutmann, David H. aut Kettenmann, Helmut aut Semtner, Marcus aut Enthalten in Acta Neuropathologica Communications London : Biomed Central, 2013 11(2023), 1 vom: 09. März (DE-627)746066465 (DE-600)2715589-4 2051-5960 nnns volume:11 year:2023 number:1 day:09 month:03 https://dx.doi.org/10.1186/s40478-023-01525-w kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2005 GBV_ILN_2009 GBV_ILN_2014 GBV_ILN_2055 GBV_ILN_2111 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 11 2023 1 09 03
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author	Logiacco, Francesca
spellingShingle	Logiacco, Francesca misc Neurofibromin misc NF1 misc Purinergic signaling misc Sex differences misc Microglia misc Cortex misc Genetically engineered mice Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
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topic_title	Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic Neurofibromin (dpeaa)DE-He213 NF1 (dpeaa)DE-He213 Purinergic signaling (dpeaa)DE-He213 Sex differences (dpeaa)DE-He213 Microglia (dpeaa)DE-He213 Cortex (dpeaa)DE-He213 Genetically engineered mice (dpeaa)DE-He213
topic	misc Neurofibromin misc NF1 misc Purinergic signaling misc Sex differences misc Microglia misc Cortex misc Genetically engineered mice
topic_unstemmed	misc Neurofibromin misc NF1 misc Purinergic signaling misc Sex differences misc Microglia misc Cortex misc Genetically engineered mice
topic_browse	misc Neurofibromin misc NF1 misc Purinergic signaling misc Sex differences misc Microglia misc Cortex misc Genetically engineered mice
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title	Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
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title_full	Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
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author_browse	Logiacco, Francesca Grzegorzek, Laura Cathleen Cordell, Elizabeth C. Popp, Oliver Mertins, Philipp Gutmann, David H. Kettenmann, Helmut Semtner, Marcus
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title_sort	neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
title_auth	Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
abstract	Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. © The Author(s) 2023
abstractGer	Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. © The Author(s) 2023
abstract_unstemmed	Abstract We previously discovered a sex-by-genotype defect in microglia function using a heterozygous germline knockout mouse model of Neurofibromatosis type 1 (Nf1 ± mice), in which only microglia from male Nf1 ± mice exhibited defects in purinergic signaling. Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. Collectively, these data reveal that Nf1 ± sexually dimorphic microglia abnormalities are likely not cell-intrinsic properties, but rather reflect a response to Nf1 heterozygosity in other brain cells. © The Author(s) 2023
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title_short	Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic
url	https://dx.doi.org/10.1186/s40478-023-01525-w
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author2	Grzegorzek, Laura Cathleen Cordell, Elizabeth C. Popp, Oliver Mertins, Philipp Gutmann, David H. Kettenmann, Helmut Semtner, Marcus
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up_date	2024-07-04T01:32:17.576Z
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Herein, we leveraged an unbiased proteomic approach to demonstrate that male, but not female, heterozygous Nf1 ± microglia exhibit differences in protein expression, which largely reflect pathways involved in cytoskeletal organization. In keeping with these predicted defects in cytoskeletal function, only male Nf1 ± microglia had reduced process arborization and surveillance capacity. To determine whether these microglial defects were cell autonomous or reflected adaptive responses to Nf1 heterozygosity in other cells in the brain, we generated conditional microglia Nf1-mutant knockout mice by intercrossing Nf1flox/flox with Cx3cr1-$ Cre^{ER} $ mice (Nf1flox/wt; Cx3cr1-$ Cre^{ER} $ mice, Nf1MG ± mice). Surprisingly, neither male nor female Nf1MG ± mouse microglia had impaired process arborization or surveillance capacity. In contrast, when Nf1 heterozygosity was generated in neurons, astrocytes and oligodendrocytes by intercrossing Nf1flox/flox with hGFAP-Cre mice (Nf1flox/wt; hGFAP-Cre mice, Nf1GFAP ± mice), the microglia defects found in Nf1 ± mice were recapitulated. 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Neurofibromatosis type 1-dependent alterations in mouse microglia function are not cell-intrinsic

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