Interactions between the secreted protein Amalgam, its transmembrane receptor Neurotactin and the Abelson tyrosine kinase affect axon pathfinding

Liebl, Eric C.; Rowe, R. Grant; Forsthoefel, David J.; Stammler, Amanda L.; Schmidt, Erica R.; Turski, Michelle L.; Seeger, Mark A.

doi:10.1242/dev.00545

Cited by 42 publications

(52 citation statements)

References 47 publications

(67 reference statements)

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“…The Drosophila ortholog dDisabled was first identified as a genetic interactor of Abl in neuron development (34). However, a more recent study indicates that the mutations in Disabled were incorrectly mapped in the prior study (35), and thus the Disabled mutant phenotype in Drosophila is not known. In Caenorhabditis elegans, the Disabled ortholog was shown to coordinate selection of lipoprotein-related receptors and cargos in the secretory trafficking pathway and the mutant is deficient in efficient secretion of proteins, including the C. elegans fibroblast growth factor (36).…”

Section: Discussionmentioning

confidence: 99%

Disabled-2 Is an Epithelial Surface Positioning Gene

Yang¹,

Cai

Roland

et al. 2007

Journal of Biological Chemistry

116

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The formation of the primitive endoderm layer on the surface of the inner cell mass is one of the earliest epithelial morphogenesis in mammalian embryos. In mouse embryos deficient of Disabled-2 (Dab2), the primitive endoderm cells lose the ability to position on the surface, resulting in defective morphogenesis. Embryonic stem cells lacking Dab2 are also unable to position on the surface of cell aggregates and fail to form a primitive endoderm outer layer in the embryoid bodies. The cellular function of Dab2, a cargo-selective adaptor, in mediating endocytic trafficking of clathrin-coated vesicles is well established. We show here that Dab2 mediates directional trafficking and polarized distribution of cell surface proteins such as megalin and E-cadherin and propose that loss of polarity is the underlying mechanism for the loss of epithelial cell surface positioning in Dab2-deficient embryos and embryoid bodies. Thus, the findings indicate that Dab2 is a surface positioning gene and suggest a novel mechanism of epithelial cell surface targeting.Epithelial cells are positioned on the outer surface of organs or the inner surface of glandular structures and are involved in diverse physiological functions. Simple epithelia consist of monolayered cells that form a sheet through cell-cell adherens junctions and attach to a basement membrane that lies underneath (1). Epithelial cells are polarized with the apical surface exposed, or free from cell-cell contact and the basal side lying in contact with a basement membrane or stromal cells. The cellfree apical space and basal contact are unique hallmarks of an epithelium and are likely positioning cues for the surface localization of the epithelial cells (2), although the molecular details and genes critical for epithelial cell surface positioning are yet uncertain and undefined. The concept that cues are required for epithelial surface positioning is also reinforced by observations of the disorganized growth of carcinomas. Carcinoma cells can be viewed as epithelial cells that have lost their ability to perceive surface positioning cues, and the neoplastic cells no longer obey the constraint imposed by tissue organization (3).The early embryos of vertebrates, especially mammalian species, have great plasticity, and significant cell dispersal, movement, and migration occur before their final positioning and acquisition of cell fates (4). Shown in the classical cell sorting experiments by Townes and Holtfreter (5), early embryonic amphibian cells of epidermis, endoderm, mesoderm, and neural plate, if dispersed, are able to segregate spontaneously upon aggregation, indicating cell positioning is an autonomous property.The primitive endoderm of mammalian early embryos is the first typical epithelial cell type derived that is capable of producing a basement membrane (6). Recent understanding is that the primitive endoderm cells arise from the differentiation of the pluripotent cells of the inner cell mass and migrate out to the surface to form the primitive endoderm layer (7...

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Section: Discussionmentioning

confidence: 99%

Disabled-2 Is an Epithelial Surface Positioning Gene

Yang¹,

Cai

Roland

et al. 2007

Journal of Biological Chemistry

116

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“…In flies, dAbl is enriched in developing axons (Bennett and Hoffmann, 1992), where it regulates the development of proper central nervous system (CNS) structure (Crowner et al, 2003;Dorsten et al, 2007;Elkins et al, 1990;Gertler et al, 1989;Giniger, 1998;Liebl et al, 2000;Liebl et al, 2003;Wills et al, 2002). Altering Abl function can lead to defects in axon attractant responses (Forsthoefel et al, 2005), repellent responses (Hsouna et al, 2003;Lee et al, 2004;Wills et al, 2002), and defasciculation and turning responses (Wills et al, 1999a;Wills et al, 1999b) (Fig.…”

Section: Journal Of Cell Science 122 (19)mentioning

confidence: 99%

Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts

Bradley

Koleske

2009

Journal of Cell Science

156

203

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The Abl-family non-receptor tyrosine kinases are essential regulators of the cytoskeleton. They transduce diverse extracellular cues into cytoskeletal rearrangements that have dramatic effects on cell motility and morphogenesis. Recent biochemical and genetic studies have revealed several mechanisms that Abl-family kinases use to mediate these effects. Abl-family kinases stimulate actin polymerization through the activation of cortactin, hematopoietic lineage cell-specific protein (HS1), WASp-and WAVE-family proteins, and Rac1. They also attenuate cell contractility by inhibiting RhoA and altering adhesion dynamics. These pathways impinge on several physiological processes, including development and maintenance of the nervous and immune systems, and epithelial morphogenesis. Elucidating how Abl-family kinases are regulated, and where and when they coordinate cytoskeletal changes, is essential for garnering a better understanding of these complex processes.

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“…In Drosophila, the disabled (dab) gene, the founding member of the dab gene family, was first identified in a screen for genetic modifiers of abelson (5). Although putative dab mutations were subsequently mapped to a different gene (6), recent studies have established functional interactions of Drosophila DISABLED (dDAB) and ABELSON (7). Proteins closely related to dDAB, including mouse DAB-2 (mDAB-2) and the single Caenorhabditis elegans family member ceDAB-1, function as CLATHRIN-associated adaptors in endocytic trafficking of cell surface receptors (8)(9)(10).…”

mentioning

confidence: 99%

The DISABLED protein functions in CLATHRIN-mediated synaptic vesicle endocytosis and exoendocytic coupling at the active zone

Kawasaki

Iyer

Posey

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Members of the DISABLED (DAB) family of proteins are known to play a conserved role in endocytic trafficking of cell surface receptors by functioning as monomeric CLATHRIN-associated sorting proteins that recruit cargo proteins into endocytic vesicles. Here, we report a Drosophila disabled mutant revealing a novel role for DAB proteins in chemical synaptic transmission. This mutant exhibits impaired synaptic function, including a rapid activitydependent reduction in neurotransmitter release and disruption of synaptic vesicle endocytosis. In presynaptic boutons, Drosophila DAB and CLATHRIN were highly colocalized within two distinct classes of puncta, including relatively dim puncta that were located at active zones and may reflect endocytic mechanisms operating at neurotransmitter release sites. Finally, broader analysis of endocytic proteins, including DYNAMIN, supported a general role for CLATHRIN-mediated endocytic mechanisms in rapid clearance of neurotransmitter release sites for subsequent vesicle priming and refilling of the release-ready vesicle pool.I ntensive study of chemical synaptic transmission has led to detailed molecular models of synaptic vesicle endocytosis (1-4). Ongoing efforts seek to define the underlying molecular components and interactions further as well as their spatial organization with respect to neurotransmitter release sites. The present study reveals novel molecular mechanisms and interactions in synaptic vesicle endocytosis involving a member of the DISABLED family of Phosphotyrosine Binding (PTB) domain proteins. In Drosophila, the disabled (dab) gene, the founding member of the dab gene family, was first identified in a screen for genetic modifiers of abelson (5). Although putative dab mutations were subsequently mapped to a different gene (6), recent studies have established functional interactions of Drosophila DISABLED (dDAB) and ABELSON (7). Proteins closely related to dDAB, including mouse DAB-2 (mDAB-2) and the single Caenorhabditis elegans family member ceDAB-1, function as CLATHRIN-associated adaptors in endocytic trafficking of cell surface receptors (8-10). These DABs have been shown to interact with CLATHRIN, the α-ADAPTIN (AP-2) adaptor complex, and other components of the endocytic machinery through conserved binding motifs (8-10) (Fig. 1A). Notably, mDAB-2, ceDAB-1, and dDAB share a PTB/DAB Homology (DH) domain near the N terminus (Fig. 1B), which interacts with specific vesicle cargo proteins and phosphatidylinositol-4,5-diphosphate (11, 12). Neither DAB proteins nor PTB domain interactions have been previously implicated in synaptic vesicle trafficking.The present study reveals a role for DAB proteins in synaptic vesicle endocytosis and extends previous work on interactions of endocytic and exocytic mechanisms in neurotransmitter release. Here, we use a glutamatergic neuromuscular synapse of the Drosophila adult as a model for genetic analysis of molecular mechanisms determining conserved properties of glutamatergic synapse function (13,14). Previous analysis i...

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Interactions between the secreted protein Amalgam, its transmembrane receptor Neurotactin and the Abelson tyrosine kinase affect axon pathfinding

Cited by 42 publications

References 47 publications

Disabled-2 Is an Epithelial Surface Positioning Gene

Disabled-2 Is an Epithelial Surface Positioning Gene

Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts

The DISABLED protein functions in CLATHRIN-mediated synaptic vesicle endocytosis and exoendocytic coupling at the active zone

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