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The Abelson tyrosine kinase regulates Notch endocytosis and signaling to maintain neuronal cell fate in Drosophila photoreceptors.

ABSTRACT: The development of a functional organ requires coordinated programs of cell fate specification, terminal differentiation and morphogenesis. Whereas signaling mechanisms that specify individual cell fates are well documented, little is known about the pathways and molecules that maintain these fates stably as normal development proceeds or how their dysregulation may contribute to altered cell states in diseases such as cancer. In Drosophila, the tyrosine kinase Abelson (Abl) interfaces with multiple signaling pathways to direct epithelial and neuronal morphogenesis during embryonic and retinal development. Here we show that Abl is required for photoreceptor cell fate maintenance, as Abl mutant photoreceptors lose neuronal markers during late pupal stages but do not re-enter a proliferative state or undergo apoptosis. Failure to maintain the differentiated state correlates with impaired trafficking of the Notch receptor and ectopic Notch signaling, and can be suppressed by reducing the genetic dose of Notch or of its downstream transcriptional effector Suppressor of Hairless. Together, these data reveal a novel mechanism for maintaining the terminally differentiated state of Drosophila photoreceptors and suggest that neuronal fates in the fly retina retain plasticity late into development. Given the general evolutionary conservation of developmental signaling mechanisms, Abl-mediated regulation of Notch could be broadly relevant to cell fate maintenance and reprogramming during normal development, regeneration and oncogenic transformation.

SUBMITTER: Xiong W

PROVIDER: S-EPMC3513998 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Abelson tyrosine kinase is required for Drosophila photoreceptor morphogenesis and retinal epithelial patterning.

Project description:Coordinated differentiation and morphogenesis transform the Drosophila retina from a layer of epithelial cells into a complex three-dimensional organ. In this study we show that the Abelson (Abl) tyrosine kinase localizes to the dynamically remodeling apical-junctional membrane domains of the developing photoreceptor cells. Analyses of abl mutant clone phenotypes demonstrate that abl is required for enriched localization of adherens junction and apical polarity complex proteins at photoreceptor-photoreceptor cell junctions and apical membrane domains, respectively, for rhabdomere generation and for spatial organization of ommatidial cells along the apical-basal axis of the epithelium. Loss of abl does not alter expression or localization of Enabled (Ena) nor does heterozygosity for ena dominantly suppress the abl phenotypes, suggesting the downstream effector mechanisms used by Abl in the eye may differ from those used in the embryo. Together our results reveal a prominent role for Abl in coordinating multiple aspects of photoreceptor morphogenesis.

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Abelson kinase regulates epithelial morphogenesis in Drosophila.

Project description:Activation of the nonreceptor tyrosine kinase Abelson (Abl) contributes to the development of leukemia, but the complex roles of Abl in normal development are not fully understood. Drosophila Abl links neural axon guidance receptors to the cytoskeleton. Here we report a novel role for Drosophila Abl in epithelial cells, where it is critical for morphogenesis. Embryos completely lacking both maternal and zygotic Abl die with defects in several morphogenetic processes requiring cell shape changes and cell migration. We describe the cellular defects that underlie these problems, focusing on dorsal closure as an example. Further, we show that the Abl target Enabled (Ena), a modulator of actin dynamics, is involved with Abl in morphogenesis. We find that Ena localizes to adherens junctions of most epithelial cells, and that it genetically interacts with the adherens junction protein Armadillo (Arm) during morphogenesis. The defects of abl mutants are strongly enhanced by heterozygosity for shotgun, which encodes DE-cadherin. Finally, loss of Abl reduces Arm and alpha-catenin accumulation in adherens junctions, while having little or no effect on other components of the cytoskeleton or cell polarity machinery. We discuss possible models for Abl function during epithelial morphogenesis in light of these data.

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miRNA suppression of a Notch repressor directs non-neuronal fate in Drosophila mechanosensory organs.

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Abelson tyrosine kinase facilitates Salmonella enterica serovar Typhimurium entry into epithelial cells.

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Raf-1, actin dynamics, and abelson tyrosine kinase in human airway smooth muscle cells.

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Drosophila Abelson kinase mediates cell invasion and proliferation through two distinct MAPK pathways.

Project description:The Abelson (Abl) family of non-receptor tyrosine kinases has an important role in cell morphogenesis, motility, and proliferation. Although the function of Abl has been extensively studied in leukemia, its role in epithelial cell invasion remains obscure. Using the Drosophila wing epithelium as an in vivo model system, we show that overexpression (activation) of Drosophila Abl (dAbl) causes loss of epithelial apical/basal cell polarity and secretion of matrix metalloproteinases, resulting in a cellular invasion and apoptosis. Our in vivo data indicate that dAbl acts downstream of the Src kinases, which are known regulators of cell adhesion and invasion. Downstream of dAbl, Rac GTPases activate two distinct MAPK pathways: c-Jun N-terminal kinase signaling (required for cell invasion and apoptosis) and ERK signaling (inducing cell proliferation). Activated Abl also increases the activity of Src members through a positive feedback loop leading to signal amplification. Thus, targeting Src-Abl, using available dual inhibitors, could be of therapeutic importance in tumor cell metastasis.

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UVRAG is required for organ rotation by regulating Notch endocytosis in Drosophila.

Project description:Heterotaxy characterized by abnormal left-right body asymmetry causes diverse congenital anomalies. Organ rotation is a crucial developmental process to establish the left-right patterning during animal development. However, the molecular basis of how organ rotation is regulated is poorly understood. Here we report that Drosophila UV-resistance associated gene (UVRAG), a tumor suppressor that regulates autophagy and endocytosis, plays unexpected roles in controlling organ rotation. Loss-of-function mutants of UVRAG show seriously impaired organ rotation phenotypes, which are associated with defects in endocytic trafficking rather than autophagy. Blunted endocytic degradation by UVRAG deficiency causes endosomal accumulation of Notch, resulting in abnormally enhanced Notch activity. Knockdown of Notch itself or expression of a dominant negative form of Notch transcriptional co-activator Mastermind is sufficient to rescue the rotation defect in UVRAG mutants. Consistently, UVRAG-mutated heterotaxy patient cells also display highly increased Notch protein levels. These results suggest evolutionarily conserved roles of UVRAG in organ rotation by regulating Notch endocytic degradation.

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Interactions with the Abelson tyrosine kinase reveal compartmentalization of eyes absent function between nucleus and cytoplasm.

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Effect of asciminib and vitamin K2 on Abelson tyrosine-kinase-inhibitor-resistant chronic myelogenous leukemia cells.

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| S-EPMC10478393 | biostudies-literature

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