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Arefin, B.

Publications and source records attributed to Arefin, B..

4 recordsLinked to original sources

Scavenger receptor endocytosis controls apical membrane morphogenesis in the Drosophila airways

The acquisition of distinct branch sizes and shapes is a central aspect in tubular organ morphogenesis and function. In the Drosophila airway tree, the interplay of apical ECM components with the underlying membrane and cytoskeleton controls tube elongation, but the link between ECM composition with apical membrane morphogenesis and tube size regulation is elusive. Here, we characterized Emp (epithelial membrane protein), a Drosophila CD36-homologue belonging to the scavenger receptor class B protein-family. emp mutant embryos fail to internalize the luminal chitin deacetylases Serp and Verm at the final stages of airway maturation and die at hatching with liquid filled airways. Emp localizes in apical epithelial membranes and shows cargo selectivity for LDLr-domain containing proteins. emp mutants also display over elongated tracheal tubes with increased levels of the apical proteins Crb, DE-cad and phosphorylated Src (p-Src). We show that Emp associates and organizes the {beta}H-Spectrin cytoskeleton and is itself confined by apical F-actin bundles. Overexpression or loss of its cargo protein Serp lead to abnormal apical accumulations of Emp and perturbations in p-Src levels. We propose that during morphogenesis, Emp senses and responds to luminal cargo levels by initiating apical membrane endocytosis along the longitudinal tube axis and thereby restricts airway elongation.

developmental biology↗

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

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 orthologues of the human oncogenic mutations ALKF1174L and ALKY1278S in the Drosophila Alk locus. AlkF1251L and AlkY1355S mutant Drosophila exhibit enhanced Alk signaling phenotypes, but unexpectedly depend on the Jelly belly (Jeb) ligand for activation. Both AlkF1251L and AlkY1355S mutant larval brains display hyperplasia, represented by increased numbers of Alk-positive neurons. Despite this hyperplasic phenotype, no brain tumors were observed in mutant animals. We show 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 (scRNA-seq), we identify 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 activating Alk mutations to perturb specification and promote survival in neuronal lineages.

cancer biology↗

DamID transcriptional profiling identifies the Snail/Scratch transcription factor Kahuli as Alk target in the Drosophila visceral mesoderm.

Development of the midgut visceral muscle of Drosophila crucially depends on Anaplastic Lymphoma Kinase (Alk) receptor tyrosine kinase (RTK) signalling, which is needed to specify founder cells (FCs) in the circular visceral mesoderm (VM). While activation of the Alk receptor by its ligand Jelly Belly (Jeb) is well characterized, only a small number of target molecules have been identified. Here, we assayed RNA polymerase II (Pol II) occupancy in VM cells by using the targeted DamID (TaDa) approach. To identify Alk targets we employed comparative analysis of embryos overexpressing Jeb versus embryos with abrogated Alk activity, revealing differential expression of a number of genes, including the Snail/Scratch family transcription factor Kahuli (Kah). Upon further in vivo validation, we confirmed that Alk signalling regulates Kah mRNA expression in the VM. We show that Kah mutants display defects in the formation of midgut constrictions, similar to that of pointed (pnt) mutants. Analysis of publicly available ChIP data defined a Kah target-binding site similar to that of Snail. In addition, we compared genes that were differentially expressed in Kah mutants with publicly available Kah- and Pnt-ChIP datasets identifying a set of common target genes putatively regulated by Kah and Pnt in midgut constriction. Taken together, we (i) report a rich dataset of Alk responsive loci in the embryonic VM, (ii) provide the first functional characterization of the Kah transcription factor, identifying a role in embryonic midgut constriction, and (iii) suggest a model in which Kah and Pnt cooperate in embryonic midgut morphogenesis.

developmental biology↗

Drosophila Neuroblast Selection Gated by Notch, Snail, SoxB and EMT Gene Interplay

In the developing Drosophila central nervous system neural progenitor (neuroblast; NB) selection is gated by lateral inhibition, controlled by Notch signalling and proneural genes. However, proneural mutants only display partial NB reduction, indicating the existence of additional genes with proneural activity. In addition, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signalling and the EMT machinery is unclear. We find that the SoxB gene SoxNeuro and the Snail gene worniou are integrated with the Notch pathway, and constitute the missing proneural genes. Notch signalling, the proneural, SoxNeuro, and worniou genes regulate key EMT genes to orchestrate the NB specification process. Hence, we uncover an expanded lateral inhibition network for NB specification, and demonstrate its link to key players in the EMT machinery. Because of the evolutionary conservation of the genes involved, the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.

developmental biology↗