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dc.contributor.author
Mannino, Maria Constanza
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dc.contributor.author
Cassidy, Mercedes Bartels
dc.contributor.author
Florez, Steven
dc.contributor.author
Rusan, Zeid
dc.contributor.author
Chakraborty, Shalini
dc.contributor.author
Schoborg, Todd
dc.date.available
2024-02-15T11:02:01Z
dc.date.issued
2023-10
dc.identifier.citation
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
dc.identifier.issn
0016-6731
dc.identifier.uri
http://hdl.handle.net/11336/226935
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Genetics Society of America
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.subject
ABNORMAL SPINDLE
dc.subject
DROSOPHILA MELANOGASTER
dc.subject
IMMUNE RESPONSE
dc.subject
MCPH
dc.subject
MICROCEPHALY
dc.subject
NEURAL STEM CELL
dc.subject
NEUROBLAST
dc.subject
NEURODEVELOPMENT
dc.subject
NOTCH SIGNALING
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TEMPORAL TRANSCRIPTION FACTOR
dc.subject.classification
Biología del Desarrollo
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dc.subject.classification
Ciencias Biológicas
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dc.subject.classification
CIENCIAS NATURALES Y EXACTAS
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dc.title
Mutations in abnormal spindle disrupt temporal transcription factor expression and trigger immune responses in the Drosophila brain
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2024-02-14T15:50:43Z
dc.journal.volume
225
dc.journal.number
4
dc.journal.pagination
1-21
dc.journal.pais
Estados Unidos
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dc.description.fil
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
dc.description.fil
Fil: Cassidy, Mercedes Bartels. College Of Agriculture And Natural Resources ; University Of Wyoming;
dc.description.fil
Fil: Florez, Steven. College Of Agriculture And Natural Resources ; University Of Wyoming;
dc.description.fil
Fil: Rusan, Zeid. College Of Agriculture And Natural Resources ; University Of Wyoming;
dc.description.fil
Fil: Chakraborty, Shalini. College Of Agriculture And Natural Resources ; University Of Wyoming;
dc.description.fil
Fil: Schoborg, Todd. College Of Agriculture And Natural Resources ; University Of Wyoming;
dc.journal.title
Genetics
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dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://academic.oup.com/genetics/advance-article/doi/10.1093/genetics/iyad188/7311216
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.1093/genetics/iyad188
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