The nonreceptor tyrosine-kinase Abl is the cellular homologue of v-abl
, the transforming gene of Abelson (Abl)*
murine leukemia virus (for review see Zou and Calame, 1999
; Mauro and Druker, 2001
). Bcr-Abl, an activated, chimeric form of Abl resulting from a chromosomal translocation, plays a causative role in human chronic myelogenous and acute lymphocytic leukemia. Bcr-Abl has deregulated tyrosine kinase activity, and an inhibitor of this kinase has shown promise in treating leukemia. Multiple substrates for oncogenic Abl kinase in diverse signaling pathways have been identified, revealing complex effects of Abl misregulation.
Abl's normal role has remained more elusive. Abl homologues are found in all animals. All share conserved NH2
-terminal SH3, SH2, and tyrosine kinase domains, as well as distinct COOH-terminal F- and G-actin binding domains (for review see Lanier and Gertler, 2000
). Mammalian Abl, unlike its fly homologue, also contains nuclear import and export signals and a COOH-terminal DNA binding domain, and thus it localizes to both nuclei and the cytoplasm. In nuclei, it is thought to regulate the cell cycle and the response to DNA damage (for review see Van Etten, 1999
). Cytoplasmic Abl predominantly associates with the actin cytoskeleton (e.g., van Etten et al., 1994
) and can be found at cell–matrix junctions in cultured cells (Lewis et al., 1996
). The different subcellular pools of Abl may perform distinct functions, though Abl can translocate to nuclei in response to cytoplasmic cues (Lewis et al., 1996
). Bcr-Abl exclusively localizes to the cytoplasm, suggesting that its role in oncogenesis involves cytoplasmic targets.
, Abl localizes to the axons of the central nervous system (CNS) (Bennett and Hoffmann, 1992
). In epithelial cells, Abl's localization varies with stage of development and tissue, but it is often concentrated near the apical cortex. Abl localizes to apical cell junctions soon after cells form and to the apical cytoplasm during gastrulation and in imaginal discs. In contrast, it is diffusely cytoplasmic in extended germband embryos.
Genetic analyses in mice and flies have begun to shed light on Abl's biological function. abl
mutant mice are embryonic-viable but runted and exhibit defects in development of the bones, immune system, and sperm. A null mutation and a COOH-terminal truncation removing the actin binding domains have similar phenotypes, suggesting that the interaction with actin is functionally important (for review see Van Etten, 1999
). Analysis of Abl function in mice is complicated by the presence of the related kinase Arg; mice lacking both abl
die as embryos with defects in neurulation that may reflect problems in actin organization (Koleske et al., 1998
, analysis of the single Abl homologue primarily revealed roles in neural development. abl
mutants are pupal lethal with defects in retinal development (Henkemeyer et al., 1987
); they also have subtle CNS defects in which certain axons stop short of innervating their target muscles (Wills et al., 1999b
). Much more severe CNS defects are seen in abl
mutants that are also heterozygous or homozygous for the neural cell adhesion molecule fasciclin
, the receptor tyrosine phosphatase dLAR
, the axon guidance receptor robo,
the adaptor disabled (dab)
, the Rho-family GEF trio
, or the actin regulator profilin
(for review see Lanier and Gertler, 2000
). These data led to a model in which Abl transduces signals from neural cell surface receptors, influencing actin dynamics in growth cones.
In doing so, Abl is thought to act via one of its substrates, Enabled (Ena; Comer et al., 1998
). Originally identified as a suppressor of abl; dab/
+ mutants (Gertler et al., 1990
), Ena is a member of the Ena/VASP family (for review see Lanier and Gertler, 2000
), which modulate actin dynamics (Gertler et al., 1996
). Drosophila ena
mutants are embryonic lethal with defects in the CNS and its peripheral projections (Gertler et al., 1990
; Wills et al., 1999a
). The effects of ena
mutations are opposite to those of abl;
axons go past their muscle targets rather than stopping short, consistent with the idea that Abl negatively regulates Ena. Like Abl, Ena is thought to act downstream of the axon guidance receptors Robo (Bashaw et al., 2000
) and dLAR (Wills et al., 1999a
), mediating cytoskeletal events.
Our interest in abl
emerged from its genetic interactions with the adherens junction protein Armadillo (Arm; Loureiro and Peifer, 1998
). We investigate morphogenesis, the process by which animals create their complex body plans by organized cell shape changes and rearrangements. Epithelial cells must remain in intimate contact throughout morphogenesis, and in order to change shape or move must coordinate their actin cytoskeletons. Cells accomplish these tasks via cell–cell adherens junctions, which form a continuous adhesive belt around the apex of each cell that anchors a contractile ring of actin filaments (for review see Tepass et al., 2000
). Junctions are organized around transmembrane cadherins. Human E-cadherin mediates cell–cell adhesion and organizes a multiprotein complex of catenins bound to its cytoplasmic tail, binding directly to β-catenin, which in turn anchors actin via interactions with α-catenin. Drosophila
E-cadherin, Arm (the β-catenin homologue), and α-catenin function similarly.
Cadherin-catenin–mediated adhesion must be dynamic, allowing cell movement during morphogenesis (for review see Tepass et al., 2000
). We used a genetic approach in Drosophila
to identify regulators of epithelial morphogenesis. abl
mutations substantially enhance the CNS defects of arm
mutants. Further, abl
genetically interacts with arm
in the epidermis (Loureiro and Peifer, 1998
). This suggested that Abl acts in epidermal cells during morphogenesis. Thus, we investigated whether Abl regulates epithelial development in Drosophila
. Previous studies of Abl function relied on zygotic mutations, and thus the maternal contribution of Abl may have masked roles in other developmental processes. We removed this maternal contribution, analyzing abl
maternal/zygotic mutants. This revealed a requirement for Abl in epithelial morphogenesis. Here we report the characterization of this role.