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
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/226935
Ver los metadatos del registro completo
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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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1844614443944640512 |
score |
13.070432 |