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Neuroblastoma-associated mutations in Drosophila Alk peturb neuronal differentiation and promote neuronal survival.

ABSTRACT: 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

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE198850 | GEO | 2022/06/27

REPOSITORIES: GEO

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