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| Status |
Public on Jun 27, 2022 |
| Title |
Neuroblastoma-associated mutations in Drosophila Alk peturb neuronal differentiation and promote neuronal survival. |
| Organism |
Drosophila melanogaster |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Activating mutations in the Anaplastic Lymphoma Kinase (ALK) receptor tyrosine kinase (RTK) are found in pediatric neuroblastoma, where they are often associated with poor prognosis. To study the effects of ALK-activating mutations in a genetically controllable system we employed CRIPSR/Cas9 to incorporate orthologues of the oncogenic human driver mutations ALKF1174 and ALKY1278S in the Drosophila Alk locus. AlkF1251 and AlkY1355S mutant Drosophila exhibit phenotypes similar to that previously associated with enhanced Alk signaling. Unexpectedly, both mutant alleles are still dependent on the presence of Jeb ligand for activation, as neither can rescue mutants of the Alk ligand Jeb. However, both Alk mutant third instar brains display hyperplasia, represented by increased numbers of Alk-positive neuronal populations. Despite this hyperplasic phenotype within the central brain area, no brain tumors were observed in mutant animals. Further investigation indicated that larval brain hyperplasia in Alk mutants was not caused by significantly increased rates of proliferation, but rather by decreased levels of apoptosis in the larval brain. Using single cell RNA sequencing (scRNAseq) analysis, we identify maintained neuronal fate change during the temporal fate specification of in the mushroom body lineages, with AlkY1355S mutants displaying precocious a’b’ neuron identity. These findings shed important light on the role of Alk in perturbation of neurodevelopmental processes and highlight the potential of activating Alk mutations to promote survival in neuronal lineages
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| Overall design |
To investigate the effect of the AlkY1355S mutation from Drosophila melanogaser third instar larval brains of control (w1118) and AlkY1355S alleles using single cell RNA sequencing (scRNAseq), employing 10X genomics.
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| Contributor(s) |
Palmer R, Anthonydhason V, Pfeifer K, Arefin B, Garcia Patricia M |
| Citation(s) |
35972154 |
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| Submission date |
Mar 17, 2022 |
| Last update date |
Aug 31, 2022 |
| Contact name |
Vimala Anthonydhason |
| Organization name |
University of Gothenburg
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| Department |
Institute of Biomedicine
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| Street address |
Medicinaregatan 9 a-b
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| City |
Göteborg |
| ZIP/Postal code |
41390 |
| Country |
Sweden |
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| Platforms (1) |
| GPL19132 |
Illumina NextSeq 500 (Drosophila melanogaster) |
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| Samples (2) |
| GSM5957926 |
SampleID_1: Wild type (WT) third instar larval brain data |
| GSM5957927 |
SampleID_2: Gain of Function (GOF) third instar larval brain data |
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| Relations |
| BioProject |
PRJNA817171 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE198850_RAW.tar |
77.9 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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