Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus
- Autores
- Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; Shuai, Bing; Attaluri, Sahithi; Takata, Yoko; Shen, Jianjun; Abba, Martín Carlos; Shetty, Ashok K.; Aldaz, Claudio Marcelo
- Año de publicación
- 2019
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.
Fil: Hussain, Tabish. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Hattiangady, Bharathi. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Kodali, Maheedhar. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Shuai, Bing. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Attaluri, Sahithi. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Takata, Yoko. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Shen, Jianjun. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos
Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina
Fil: Shetty, Ashok K.. Texas A&M Health Science Center College of Medicine; Estados Unidos
Fil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos - Materia
-
ASTROGLIOSIS
EPILEPSY
GABA-ERGIC INTERNEURONS
HIPPOCAMPUS
MICROGLIOSIS
WWOX - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-nd/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/105075
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Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampusHussain, TabishKil, HyunsukHattiangady, BharathiLee, JaehoKodali, MaheedharShuai, BingAttaluri, SahithiTakata, YokoShen, JianjunAbba, Martín CarlosShetty, Ashok K.Aldaz, Claudio MarceloASTROGLIOSISEPILEPSYGABA-ERGIC INTERNEURONSHIPPOCAMPUSMICROGLIOSISWWOXhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain.Fil: Hussain, Tabish. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Hattiangady, Bharathi. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Kodali, Maheedhar. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Shuai, Bing. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Attaluri, Sahithi. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Takata, Yoko. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Shen, Jianjun. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosFil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; ArgentinaFil: Shetty, Ashok K.. Texas A&M Health Science Center College of Medicine; Estados UnidosFil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados UnidosAcademic Press Inc Elsevier Science2019-01info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/105075Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; et al.; Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus; Academic Press Inc Elsevier Science; Neurobiology of Disease; 121; 1-2019; 163-1760969-9961CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2018.09.026info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996118306612info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-nd/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:42:36Zoai:ri.conicet.gov.ar:11336/105075instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:42:37.201CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
title |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
spellingShingle |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus Hussain, Tabish ASTROGLIOSIS EPILEPSY GABA-ERGIC INTERNEURONS HIPPOCAMPUS MICROGLIOSIS WWOX |
title_short |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
title_full |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
title_fullStr |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
title_full_unstemmed |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
title_sort |
Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus |
dc.creator.none.fl_str_mv |
Hussain, Tabish Kil, Hyunsuk Hattiangady, Bharathi Lee, Jaeho Kodali, Maheedhar Shuai, Bing Attaluri, Sahithi Takata, Yoko Shen, Jianjun Abba, Martín Carlos Shetty, Ashok K. Aldaz, Claudio Marcelo |
author |
Hussain, Tabish |
author_facet |
Hussain, Tabish Kil, Hyunsuk Hattiangady, Bharathi Lee, Jaeho Kodali, Maheedhar Shuai, Bing Attaluri, Sahithi Takata, Yoko Shen, Jianjun Abba, Martín Carlos Shetty, Ashok K. Aldaz, Claudio Marcelo |
author_role |
author |
author2 |
Kil, Hyunsuk Hattiangady, Bharathi Lee, Jaeho Kodali, Maheedhar Shuai, Bing Attaluri, Sahithi Takata, Yoko Shen, Jianjun Abba, Martín Carlos Shetty, Ashok K. Aldaz, Claudio Marcelo |
author2_role |
author author author author author author author author author author author |
dc.subject.none.fl_str_mv |
ASTROGLIOSIS EPILEPSY GABA-ERGIC INTERNEURONS HIPPOCAMPUS MICROGLIOSIS WWOX |
topic |
ASTROGLIOSIS EPILEPSY GABA-ERGIC INTERNEURONS HIPPOCAMPUS MICROGLIOSIS WWOX |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/1.6 https://purl.org/becyt/ford/1 |
dc.description.none.fl_txt_mv |
The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain. Fil: Hussain, Tabish. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Kil, Hyunsuk. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Hattiangady, Bharathi. Texas A&M Health Science Center College of Medicine; Estados Unidos Fil: Lee, Jaeho. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Kodali, Maheedhar. Texas A&M Health Science Center College of Medicine; Estados Unidos Fil: Shuai, Bing. Texas A&M Health Science Center College of Medicine; Estados Unidos Fil: Attaluri, Sahithi. Texas A&M Health Science Center College of Medicine; Estados Unidos Fil: Takata, Yoko. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Shen, Jianjun. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos Fil: Abba, Martín Carlos. Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Inmunológicas Básicas y Aplicadas; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina Fil: Shetty, Ashok K.. Texas A&M Health Science Center College of Medicine; Estados Unidos Fil: Aldaz, Claudio Marcelo. University of Texas Health Science Center at Houston. University of Texas Md Anderson Cancer Center; Estados Unidos |
description |
The association of WW domain-containing oxidoreductase WWOX gene loss of function with central nervous system (CNS) related pathologies is well documented. These include spinocerebellar ataxia, epilepsy and mental retardation (SCAR12, OMIM: 614322) and early infantile epileptic encephalopathy (EIEE28, OMIM: 616211) syndromes. However, there is complete lack of understanding of the pathophysiological mechanisms at play. In this study, using a Wwox knockout (Wwox KO) mouse model (2 weeks old, both sexes) and stereological studies we observe that Wwox deletion leads to a significant reduction in the number of hippocampal GABA-ergic (γ-aminobutyric acid) interneurons. Wwox KO mice displayed significantly reduced numbers of calcium-binding protein parvalbumin (PV) and neuropeptide Y (NPY) expressing interneurons in different subfields of the hippocampus in comparison to Wwox wild-type (WT) mice. We also detected decreased levels of Glutamic Acid Decarboxylase protein isoforms GAD65/67 expression in Wwox null hippocampi suggesting lower levels of GABA synthesis. In addition, Wwox deficiency was associated with signs of neuroinflammation such as evidence of activated microglia, astrogliosis, and overexpression of inflammatory cytokines Tnf-a and Il6. We also performed comparative transcriptome-wide expression analyses of neural stem cells grown as neurospheres from hippocampi of Wwox KO and WT mice thus identifying 283 genes significantly dysregulated in their expression. Functional annotation of transcriptome profiling differences identified ?neurological disease? and ?CNS development related functions? to be significantly enriched. Several epilepsy-related genes were found differentially expressed in Wwox KO neurospheres. This study provides the first genotype-phenotype observations as well as potential mechanistic clues associated with Wwox loss of function in the brain. |
publishDate |
2019 |
dc.date.none.fl_str_mv |
2019-01 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/105075 Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; et al.; Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus; Academic Press Inc Elsevier Science; Neurobiology of Disease; 121; 1-2019; 163-176 0969-9961 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/105075 |
identifier_str_mv |
Hussain, Tabish; Kil, Hyunsuk; Hattiangady, Bharathi; Lee, Jaeho; Kodali, Maheedhar; et al.; Wwox deletion leads to reduced GABA-ergic inhibitory interneuron numbers and activation of microglia and astrocytes in mouse hippocampus; Academic Press Inc Elsevier Science; Neurobiology of Disease; 121; 1-2019; 163-176 0969-9961 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/doi/10.1016/j.nbd.2018.09.026 info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S0969996118306612 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-nd/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-nd/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Academic Press Inc Elsevier Science |
publisher.none.fl_str_mv |
Academic Press Inc Elsevier Science |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613342170185728 |
score |
13.070432 |