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| Status |
Public on Oct 06, 2023 |
| Title |
Identifying new cellular mechanisms of MCPH5 |
| Organism |
Drosophila melanogaster |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
The coordination of cellular behaviors during neurodevelopment is critical for determining the form, function, and size of the central nervous system. Mutations in the vertebrate Abnormal Spindle-Like, Microcephaly Associated (ASPM) gene and its Drosophila melanogaster ortholog abnormal spindle (asp) lead to microcephaly, 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 co-expressed genes in the developing central nervous system (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.
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| Overall design |
We sequenced bulk mRNA from the central nervous system (brain) of Drosophila melanogaster third instar larva, mid-pupal, and adult developmental stages. Three genotypes were included: Heterozygous control (aspt25/+), asp mutant (aspT25/aspDf), and a genetic resuce strain (AspMF/+; AspT25/AspDf)
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| Contributor(s) |
Mannino MC, Cassidy M, Florez S, Rusan Z, Chakraborty S, Schoborg T |
| Citation(s) |
37831641 |
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| Submission date |
Oct 02, 2023 |
| Last update date |
Jan 05, 2024 |
| Contact name |
Todd Schoborg |
| E-mail(s) |
todd.schoborg@uwyo.edu
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| Phone |
3073142115
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| Organization name |
University of Wyoming
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| Department |
Molecular Biology
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| Street address |
1000 E. University Ave, Department of Molecular Biology, #3944
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| City |
Laramie |
| State/province |
Wyoming |
| ZIP/Postal code |
82071 |
| Country |
USA |
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| Platforms (1) |
| GPL25244 |
Illumina NovaSeq 6000 (Drosophila melanogaster) |
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| Samples (36)
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| GSM7816398 |
Larval Brain, WT, Rep. 4 |
| GSM7816399 |
Larval Brain, Asp Mutant, Rep. 1 |
| GSM7816400 |
Larval Brain, Asp Mutant, Rep. 2 |
| GSM7816401 |
Larval Brain, Asp Mutant, Rep. 3 |
| GSM7816402 |
Larval Brain, Asp Mutant, Rep. 4 |
| GSM7816403 |
Larval Brain, Rescue, Rep. 1 |
| GSM7816404 |
Larval Brain, Rescue, Rep. 2 |
| GSM7816405 |
Larval Brain, Rescue, Rep. 3 |
| GSM7816406 |
Larval Brain, Rescue, Rep. 4 |
| GSM7816407 |
Pupal Brain, WT, Rep. 1 |
| GSM7816408 |
Pupal Brain, WT, Rep. 2 |
| GSM7816409 |
Pupal Brain, WT, Rep. 3 |
| GSM7816410 |
Pupal Brain, WT, Rep. 4 |
| GSM7816411 |
Pupal Brain, Asp Mutant, Rep. 1 |
| GSM7816412 |
Pupal Brain, Asp Mutant, Rep. 2 |
| GSM7816413 |
Pupal Brain, Asp Mutant, Rep. 3 |
| GSM7816414 |
Pupal Brain, Asp Mutant, Rep. 4 |
| GSM7816415 |
Pupal Brain, Rescue, Rep. 1 |
| GSM7816416 |
Pupal Brain, Rescue, Rep. 2 |
| GSM7816417 |
Pupal Brain, Rescue, Rep. 3 |
| GSM7816418 |
Pupal Brain, Rescue, Rep. 4 |
| GSM7816419 |
Adult Brain, WT, Rep. 1 |
| GSM7816420 |
Adult Brain, WT, Rep. 2 |
| GSM7816421 |
Adult Brain, WT, Rep. 3 |
| GSM7816422 |
Adult Brain, WT, Rep. 4 |
| GSM7816423 |
Adult Brain, Asp Mutant, Rep. 1 |
| GSM7816424 |
Adult Brain, Asp Mutant, Rep. 2 |
| GSM7816425 |
Adult Brain, Asp Mutant, Rep. 3 |
| GSM7816426 |
Adult Brain, Asp Mutant, Rep. 4 |
| GSM7816427 |
Adult Brain, Rescue, Rep. 1 |
| GSM7816428 |
Adult Brain, Rescue, Rep. 2 |
| GSM7816429 |
Adult Brain, Rescue, Rep. 3 |
| GSM7816430 |
Adult Brain, Rescue, Rep. 4 |
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| Relations |
| BioProject |
PRJNA1023222 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE244463_AB_edgeR_MUT-RES.tabular.txt.gz |
556.0 Kb |
(ftp)(http) |
TXT |
| GSE244463_AB_edgeR_MUT-WT.tabular.txt.gz |
571.8 Kb |
(ftp)(http) |
TXT |
| GSE244463_AB_edgeR_RES-WT.tabular.txt.gz |
548.2 Kb |
(ftp)(http) |
TXT |
| GSE244463_LB_edgeR_MUT-RES.tabular.txt.gz |
543.5 Kb |
(ftp)(http) |
TXT |
| GSE244463_LB_edgeR_MUT-WT.tabular.txt.gz |
573.0 Kb |
(ftp)(http) |
TXT |
| GSE244463_LB_edgeR_RES-WT.tabular.txt.gz |
558.1 Kb |
(ftp)(http) |
TXT |
| GSE244463_PB_edgeR_MUT-RES.tabular.txt.gz |
560.2 Kb |
(ftp)(http) |
TXT |
| GSE244463_PB_edgeR_MUT-WT.tabular.txt.gz |
561.6 Kb |
(ftp)(http) |
TXT |
| GSE244463_PB_edgeR_RES-WT.tabular.txt.gz |
585.4 Kb |
(ftp)(http) |
TXT |
| GSE244463_RAW.tar |
2.7 Mb |
(http)(custom) |
TAR (of TXT) |
SRA Run Selector |
| Raw data are available in SRA |
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