Abstract
Cell morphogenesis, which requires rearrangement of the actin cytoskeleton, is essential to coordinate the development of tissues such as the musculature and nervous system during normal embryonic development. One class of signaling proteins that regulate actin cytoskeletal rearrangement is the evolutionarily conserved CDM (C. elegans Ced-5, human DOCK180, Drosophila Myoblast city, or Mbc) family of proteins, which function as unconventional guanine nucleotide exchange factors for the small GTPase Rac. This CDM-Rac protein complex is sufficient for Rac activation, but is enhanced upon the association of CDM proteins with the ELMO/Ced-12 family of proteins. We identified and characterized the role of Drosophila Sponge (Spg), the vertebrate DOCK3/DOCK4 counterpart as an ELMO-interacting protein. Our analysis shows Spg mRNA and protein is expressed in the visceral musculature and developing nervous system, suggesting a role for Spg in later embryogenesis. As maternal null mutants of spg die early in development, we utilized genetic interaction analysis to uncover the role of Spg in central nervous system (CNS) development. Consistent with its role in ELMO-dependent pathways, we found genetic interactions with spg and elmo mutants exhibited aberrant axonal defects. In addition, our data suggests Ncad may be responsible for recruiting Spg to the membrane, possibly in CNS development. Our findings not only characterize the role of a new DOCK family member, but help to further understand the role of signaling downstream of N-cadherin in neuronal development.
Highlights
The formation of embryonic tissues is a key feature in generating diversity in animal development
ELMO-specific complexes were isolated from embryonic lysates with anti-HA resin, digested with trypsin, and analyzed by Multidimensional Protein Identification Technology (MudPIT) mass spectrometry [46]
To further examine if Spg is the only DOCK family member required for axonal patterning, we examined the potential contribution of Mbc in the developing nervous system
Summary
The formation of embryonic tissues is a key feature in generating diversity in animal development. After cell fate is established, cell-cell signaling and intracellular signal transduction pathways instruct cells to undergo cell shape changes These cell shape changes are necessary for cell movement, a basic process that underlies embryonic development and is largely accomplished by regulation of the actin cytoskeleton. One common feature of cell rearrangements via the actin cytoskeleton is the involvement of the Rho family of GTPases [3,4]. Conserved across species and involved in seemingly diverse developmental processes including cell migration, phagocytosis, and myoblast fusion, the Rho GTPases are key signaling molecules that impinge upon actin cytoskeletal reorganization [5]. It is thought that GEFs are a crucial intermediate that signal from upstream cell surface receptors to mediate GTPase activation. Trio physically interacts with the Netrin receptor Frazzled to regulate chemoattraction [8,9], while Son of sevenless (Sos) associates with the Roundabout (Robo) receptor through the SH2-SH3 adaptor protein Dreadlocks (DOCK) to control axon repulsion [9]
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