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Patient-associated mutations in Drosophila Alk perturb neuronal differentiation and promote survival

Pfeifer, Kathrin ; Wolfstetter, Georg ; Anthonydhason, Vimala ; Masudi, Tafheem ; Arefin, Badrul ; Bemark, Mats LU orcid ; Mendoza-Garcia, Patricia and Palmer, Ruth H (2022) In DMM Disease Models and Mechanisms 15(8).
Abstract

Activating anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) mutations occur in pediatric neuroblastoma and are associated with poor prognosis. To study ALK-activating mutations in a genetically controllable system, we employed CRIPSR/Cas9, incorporating orthologs of the human oncogenic mutations ALKF1174L and ALKY1278S in the Drosophila Alk locus. AlkF1251L and AlkY1355S mutant Drosophila exhibited enhanced Alk signaling phenotypes, but unexpectedly depended on the Jelly belly (Jeb) ligand for activation. Both AlkF1251L and AlkY1355S mutant larval brains displayed hyperplasia, represented by increased numbers of Alk-positive neurons. Despite this hyperplasic phenotype, no brain tumors were observed in mutant animals. We... (More)

Activating anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) mutations occur in pediatric neuroblastoma and are associated with poor prognosis. To study ALK-activating mutations in a genetically controllable system, we employed CRIPSR/Cas9, incorporating orthologs of the human oncogenic mutations ALKF1174L and ALKY1278S in the Drosophila Alk locus. AlkF1251L and AlkY1355S mutant Drosophila exhibited enhanced Alk signaling phenotypes, but unexpectedly depended on the Jelly belly (Jeb) ligand for activation. Both AlkF1251L and AlkY1355S mutant larval brains displayed hyperplasia, represented by increased numbers of Alk-positive neurons. Despite this hyperplasic phenotype, no brain tumors were observed in mutant animals. We showed that 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, we identified perturbations during temporal fate specification in AlkY1355S mutant mushroom body lineages. These findings shed light on the role of Alk in neurodevelopmental processes and highlight the potential of Alk-activating mutations to perturb specification and promote survival in neuronal lineages. This article has an associated First Person interview with the first author of the paper.

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author
; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Anaplastic Lymphoma Kinase/genetics, Animals, Cell Differentiation, Child, Drosophila Proteins/genetics, Drosophila melanogaster/genetics, Humans, Hyperplasia, Mutation, Neurons/cytology, Receptor Protein-Tyrosine Kinases/genetics, Neuroblast, Tumor, brain, Visceral mesoderm, Signaling, RTK, Neurogenesis, Neuroblastoma
in
DMM Disease Models and Mechanisms
volume
15
issue
8
pages
16 pages
publisher
The Company of Biologists Ltd
external identifiers
  • scopus:85136064879
  • pmid:35972154
ISSN
1754-8411
DOI
10.1242/dmm.049591
language
English
LU publication?
no
additional info
© 2022. Published by The Company of Biologists Ltd.
id
759a9d81-a2e0-445e-ba0a-8ee8e64545b3
date added to LUP
2023-11-16 12:45:16
date last changed
2024-04-14 17:00:02
@article{759a9d81-a2e0-445e-ba0a-8ee8e64545b3,
  abstract     = {{<p>Activating anaplastic lymphoma kinase (ALK) receptor tyrosine kinase (RTK) mutations occur in pediatric neuroblastoma and are associated with poor prognosis. To study ALK-activating mutations in a genetically controllable system, we employed CRIPSR/Cas9, incorporating orthologs of the human oncogenic mutations ALKF1174L and ALKY1278S in the Drosophila Alk locus. AlkF1251L and AlkY1355S mutant Drosophila exhibited enhanced Alk signaling phenotypes, but unexpectedly depended on the Jelly belly (Jeb) ligand for activation. Both AlkF1251L and AlkY1355S mutant larval brains displayed hyperplasia, represented by increased numbers of Alk-positive neurons. Despite this hyperplasic phenotype, no brain tumors were observed in mutant animals. We showed that 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, we identified perturbations during temporal fate specification in AlkY1355S mutant mushroom body lineages. These findings shed light on the role of Alk in neurodevelopmental processes and highlight the potential of Alk-activating mutations to perturb specification and promote survival in neuronal lineages. This article has an associated First Person interview with the first author of the paper.</p>}},
  author       = {{Pfeifer, Kathrin and Wolfstetter, Georg and Anthonydhason, Vimala and Masudi, Tafheem and Arefin, Badrul and Bemark, Mats and Mendoza-Garcia, Patricia and Palmer, Ruth H}},
  issn         = {{1754-8411}},
  keywords     = {{Anaplastic Lymphoma Kinase/genetics; Animals; Cell Differentiation; Child; Drosophila Proteins/genetics; Drosophila melanogaster/genetics; Humans; Hyperplasia; Mutation; Neurons/cytology; Receptor Protein-Tyrosine Kinases/genetics; Neuroblast; Tumor; brain; Visceral mesoderm; Signaling; RTK; Neurogenesis; Neuroblastoma}},
  language     = {{eng}},
  month        = {{08}},
  number       = {{8}},
  publisher    = {{The Company of Biologists Ltd}},
  series       = {{DMM Disease Models and Mechanisms}},
  title        = {{Patient-associated mutations in Drosophila Alk perturb neuronal differentiation and promote survival}},
  url          = {{http://dx.doi.org/10.1242/dmm.049591}},
  doi          = {{10.1242/dmm.049591}},
  volume       = {{15}},
  year         = {{2022}},
}