Abl Kinase Inhibits the Engulfment of Apopotic Cells in Caenorhabditis elegans

Michael E Hurwitz,Gian Garriga,H Robert Horvitz,Pamela J Vanderzalm,Laird Bloom,Julia Goldman,Douglas R Green

doi:10.1371/journal.pbio.1000099

Abstract

The engulfment of apoptotic cells is required for normal metazoan development and tissue remodeling. In Caenorhabditis elegans, two parallel and partially redundant conserved pathways act in cell-corpse engulfment. One pathway includes the adaptor protein CED-2 CrkII and the small GTPase CED-10 Rac, and acts to rearrange the cytoskeleton of the engulfing cell. The other pathway includes the receptor tyrosine kinase CED-1 and might recruit membranes to extend the surface of the engulfing cell. Although many components required for engulfment have been identified, little is known about inhibition of engulfment. The tyrosine kinase Abl regulates the actin cytoskeleton in mammals and Drosophila in multiple ways. For example, Abl inhibits cell migration via phosphorylation of CrkII. We tested whether ABL-1, the C. elegans ortholog of Abl, inhibits the CED-2 CrkII-dependent engulfment of apoptotic cells. Our genetic studies indicate that ABL-1 inhibits apoptotic cell engulfment, but not through CED-2 CrkII, and instead acts in parallel to the two known engulfment pathways. The CED-10 Rac pathway is also required for proper migration of the distal tip cells (DTCs) during the development of the C. elegans gonad. The loss of ABL-1 function partially restores normal DTC migration in the CED-10 Rac pathway mutants. We found that ABI-1 the C. elegans homolog of mammalian Abi (Abl interactor) proteins, is required for engulfment of apoptotic cells and proper DTC migration. Like Abl, Abi proteins are cytoskeletal regulators. ABI-1 acts in parallel to the two known engulfment pathways, likely downstream of ABL-1. ABL-1 and ABI-1 interact physically in vitro. We propose that ABL-1 opposes the engulfment of apoptotic cells by inhibiting ABI-1 via a pathway that is distinct from the two known engulfment pathways.

Highlights

Regulated reorganization of the cytoskeleton is a fundamental process in tissue morphogenesis and physiologic cell migration [1]
ABL-1 Inhibits the Engulfment of Apoptotic Cell Corpses To test whether abl-1 has a role in engulfment, we counted the number of unengulfed apoptotic cell corpses in the heads of first larval stage (L1) animals harboring mutations in abl-1 and engulfment pathway genes
Mutation of abl-1 decreased the number of unengulfed corpses in the heads of ced-1, ced-6, and ced-7 mutants (Table 1). dyn-1 mutants die as embryos and were not tested

Summary

Introduction

Regulated reorganization of the cytoskeleton is a fundamental process in tissue morphogenesis and physiologic cell migration [1]. In C. elegans, neighboring cells engulf apoptotic cells. Eleven genes appear to act in two parallel pathways required for engulfment: ced-1, ced-6, ced-7, and dyn-1; and ced, ced-5, ced-10, ced-12, mig-2, unc-73, and psr-1 (Figure 1) [3]. These two pathways have been proposed to recruit membranes for cell surface extension and rearrange the cytoskeleton, respectively. The pathways together promote the extension of the engulfing cell around the apoptotic cell

Methods

Results

Conclusion