Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain

Autores
Mannino, Maria Constanza; Cassidy, Mercedes Bartels; Florez, Steven; Rusan, Zeid; Chakraborty, Shalini; Schoborg, Todd
Año de publicación
2023
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The coordination of cellular behaviors during neurodevelopment is critical for determining the form, function, and size of the central nervous system (CNS). Mutations in the vertebrate Abnormal Spindle-Like, Microcephaly Associated (ASPM) gene and its Drosophila melanogaster ortholog abnormal spindle (asp) lead to microcephaly (MCPH), a reduction in overall brain size whose etiology remains poorly defined. Here, we provide the neurodevelopmental transcriptional landscape for a Drosophila model for autosomal recessive primary microcephaly-5 (MCPH5) and extend our findings into the functional realm to identify the key cellular mechanisms responsible for Asp-dependent brain growth and development. We identify multiple transcriptomic signatures, including new patterns of coexpressed genes in the developing CNS. Defects in optic lobe neurogenesis were detected in larval brains through downregulation of temporal transcription factors (tTFs) and Notch signaling targets, which correlated with a significant reduction in brain size and total cell numbers during the neurogenic window of development. We also found inflammation as a hallmark of asp mutant brains, detectable throughout every stage of CNS development, which also contributes to the brain size phenotype. Finally, we show that apoptosis is not a primary driver of the asp mutant brain phenotypes, further highlighting an intrinsic Asp-dependent neurogenesis promotion mechanism that is independent of cell death. Collectively, our results suggest that the etiology of the asp mutant brain phenotype is complex and that a comprehensive view of the cellular basis of the disorder requires an understanding of how multiple pathway inputs collectively determine tissue size and architecture.
Fil: Mannino, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Cassidy, Mercedes Bartels. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Florez, Steven. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Rusan, Zeid. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Chakraborty, Shalini. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Schoborg, Todd. College Of Agriculture And Natural Resources ; University Of Wyoming;
Materia
ABNORMAL SPINDLE
DROSOPHILA MELANOGASTER
IMMUNE RESPONSE
MCPH
MICROCEPHALY
NEURAL STEM CELL
NEUROBLAST
NEURODEVELOPMENT
NOTCH SIGNALING
TEMPORAL TRANSCRIPTION FACTOR
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/226935

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oai_identifier_str oai:ri.conicet.gov.ar:11336/226935
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brainMannino, Maria ConstanzaCassidy, Mercedes BartelsFlorez, StevenRusan, ZeidChakraborty, ShaliniSchoborg, ToddABNORMAL SPINDLEDROSOPHILA MELANOGASTERIMMUNE RESPONSEMCPHMICROCEPHALYNEURAL STEM CELLNEUROBLASTNEURODEVELOPMENTNOTCH SIGNALINGTEMPORAL TRANSCRIPTION FACTORhttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1The coordination of cellular behaviors during neurodevelopment is critical for determining the form, function, and size of the central nervous system (CNS). Mutations in the vertebrate Abnormal Spindle-Like, Microcephaly Associated (ASPM) gene and its Drosophila melanogaster ortholog abnormal spindle (asp) lead to microcephaly (MCPH), a reduction in overall brain size whose etiology remains poorly defined. Here, we provide the neurodevelopmental transcriptional landscape for a Drosophila model for autosomal recessive primary microcephaly-5 (MCPH5) and extend our findings into the functional realm to identify the key cellular mechanisms responsible for Asp-dependent brain growth and development. We identify multiple transcriptomic signatures, including new patterns of coexpressed genes in the developing CNS. Defects in optic lobe neurogenesis were detected in larval brains through downregulation of temporal transcription factors (tTFs) and Notch signaling targets, which correlated with a significant reduction in brain size and total cell numbers during the neurogenic window of development. We also found inflammation as a hallmark of asp mutant brains, detectable throughout every stage of CNS development, which also contributes to the brain size phenotype. Finally, we show that apoptosis is not a primary driver of the asp mutant brain phenotypes, further highlighting an intrinsic Asp-dependent neurogenesis promotion mechanism that is independent of cell death. Collectively, our results suggest that the etiology of the asp mutant brain phenotype is complex and that a comprehensive view of the cellular basis of the disorder requires an understanding of how multiple pathway inputs collectively determine tissue size and architecture.Fil: Mannino, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; ArgentinaFil: Cassidy, Mercedes Bartels. College Of Agriculture And Natural Resources ; University Of Wyoming;Fil: Florez, Steven. College Of Agriculture And Natural Resources ; University Of Wyoming;Fil: Rusan, Zeid. College Of Agriculture And Natural Resources ; University Of Wyoming;Fil: Chakraborty, Shalini. College Of Agriculture And Natural Resources ; University Of Wyoming;Fil: Schoborg, Todd. College Of Agriculture And Natural Resources ; University Of Wyoming;Genetics Society of America2023-10info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/226935Mannino, Maria Constanza; Cassidy, Mercedes Bartels; Florez, Steven; Rusan, Zeid; Chakraborty, Shalini; et al.; Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain; Genetics Society of America; Genetics; 225; 4; 10-2023; 1-210016-6731CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/genetics/advance-article/doi/10.1093/genetics/iyad188/7311216info:eu-repo/semantics/altIdentifier/doi/10.1093/genetics/iyad188info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:41:20Zoai:ri.conicet.gov.ar:11336/226935instacron: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 10:41:21.211CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
title Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
spellingShingle Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
Mannino, Maria Constanza
ABNORMAL SPINDLE
DROSOPHILA MELANOGASTER
IMMUNE RESPONSE
MCPH
MICROCEPHALY
NEURAL STEM CELL
NEUROBLAST
NEURODEVELOPMENT
NOTCH SIGNALING
TEMPORAL TRANSCRIPTION FACTOR
title_short Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
title_full Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
title_fullStr Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
title_full_unstemmed Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
title_sort Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
dc.creator.none.fl_str_mv Mannino, Maria Constanza
Cassidy, Mercedes Bartels
Florez, Steven
Rusan, Zeid
Chakraborty, Shalini
Schoborg, Todd
author Mannino, Maria Constanza
author_facet Mannino, Maria Constanza
Cassidy, Mercedes Bartels
Florez, Steven
Rusan, Zeid
Chakraborty, Shalini
Schoborg, Todd
author_role author
author2 Cassidy, Mercedes Bartels
Florez, Steven
Rusan, Zeid
Chakraborty, Shalini
Schoborg, Todd
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ABNORMAL SPINDLE
DROSOPHILA MELANOGASTER
IMMUNE RESPONSE
MCPH
MICROCEPHALY
NEURAL STEM CELL
NEUROBLAST
NEURODEVELOPMENT
NOTCH SIGNALING
TEMPORAL TRANSCRIPTION FACTOR
topic ABNORMAL SPINDLE
DROSOPHILA MELANOGASTER
IMMUNE RESPONSE
MCPH
MICROCEPHALY
NEURAL STEM CELL
NEUROBLAST
NEURODEVELOPMENT
NOTCH SIGNALING
TEMPORAL TRANSCRIPTION FACTOR
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 coordination of cellular behaviors during neurodevelopment is critical for determining the form, function, and size of the central nervous system (CNS). Mutations in the vertebrate Abnormal Spindle-Like, Microcephaly Associated (ASPM) gene and its Drosophila melanogaster ortholog abnormal spindle (asp) lead to microcephaly (MCPH), a reduction in overall brain size whose etiology remains poorly defined. Here, we provide the neurodevelopmental transcriptional landscape for a Drosophila model for autosomal recessive primary microcephaly-5 (MCPH5) and extend our findings into the functional realm to identify the key cellular mechanisms responsible for Asp-dependent brain growth and development. We identify multiple transcriptomic signatures, including new patterns of coexpressed genes in the developing CNS. Defects in optic lobe neurogenesis were detected in larval brains through downregulation of temporal transcription factors (tTFs) and Notch signaling targets, which correlated with a significant reduction in brain size and total cell numbers during the neurogenic window of development. We also found inflammation as a hallmark of asp mutant brains, detectable throughout every stage of CNS development, which also contributes to the brain size phenotype. Finally, we show that apoptosis is not a primary driver of the asp mutant brain phenotypes, further highlighting an intrinsic Asp-dependent neurogenesis promotion mechanism that is independent of cell death. Collectively, our results suggest that the etiology of the asp mutant brain phenotype is complex and that a comprehensive view of the cellular basis of the disorder requires an understanding of how multiple pathway inputs collectively determine tissue size and architecture.
Fil: Mannino, Maria Constanza. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner". Universidad Nacional de la Plata. Facultad de Ciencias Médicas. Instituto de Investigaciones Bioquímicas de La Plata "Prof. Dr. Rodolfo R. Brenner"; Argentina
Fil: Cassidy, Mercedes Bartels. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Florez, Steven. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Rusan, Zeid. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Chakraborty, Shalini. College Of Agriculture And Natural Resources ; University Of Wyoming;
Fil: Schoborg, Todd. College Of Agriculture And Natural Resources ; University Of Wyoming;
description The coordination of cellular behaviors during neurodevelopment is critical for determining the form, function, and size of the central nervous system (CNS). Mutations in the vertebrate Abnormal Spindle-Like, Microcephaly Associated (ASPM) gene and its Drosophila melanogaster ortholog abnormal spindle (asp) lead to microcephaly (MCPH), a reduction in overall brain size whose etiology remains poorly defined. Here, we provide the neurodevelopmental transcriptional landscape for a Drosophila model for autosomal recessive primary microcephaly-5 (MCPH5) and extend our findings into the functional realm to identify the key cellular mechanisms responsible for Asp-dependent brain growth and development. We identify multiple transcriptomic signatures, including new patterns of coexpressed genes in the developing CNS. Defects in optic lobe neurogenesis were detected in larval brains through downregulation of temporal transcription factors (tTFs) and Notch signaling targets, which correlated with a significant reduction in brain size and total cell numbers during the neurogenic window of development. We also found inflammation as a hallmark of asp mutant brains, detectable throughout every stage of CNS development, which also contributes to the brain size phenotype. Finally, we show that apoptosis is not a primary driver of the asp mutant brain phenotypes, further highlighting an intrinsic Asp-dependent neurogenesis promotion mechanism that is independent of cell death. Collectively, our results suggest that the etiology of the asp mutant brain phenotype is complex and that a comprehensive view of the cellular basis of the disorder requires an understanding of how multiple pathway inputs collectively determine tissue size and architecture.
publishDate 2023
dc.date.none.fl_str_mv 2023-10
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/11336/226935
Mannino, Maria Constanza; Cassidy, Mercedes Bartels; Florez, Steven; Rusan, Zeid; Chakraborty, Shalini; et al.; Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain; Genetics Society of America; Genetics; 225; 4; 10-2023; 1-21
0016-6731
CONICET Digital
CONICET
url http://hdl.handle.net/11336/226935
identifier_str_mv Mannino, Maria Constanza; Cassidy, Mercedes Bartels; Florez, Steven; Rusan, Zeid; Chakraborty, Shalini; et al.; Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain; Genetics Society of America; Genetics; 225; 4; 10-2023; 1-21
0016-6731
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/genetics/advance-article/doi/10.1093/genetics/iyad188/7311216
info:eu-repo/semantics/altIdentifier/doi/10.1093/genetics/iyad188
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Genetics Society of America
publisher.none.fl_str_mv Genetics Society of America
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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