The DOCK Protein Sponge Binds to ELMO and Functions in Drosophila Embryonic CNS Development

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.

The Atypical Guanine Nucleotide Exchange Factor Dock4 Regulates Neurite Differentiation through Modulation of Rac1 GTPase and Actin Dynamics

“…Multiple studies in fibroblasts then confirmed that Dock4 is capable of controlling cell migration by transducing several upstream signals, such as Wnt, platelet-derived growth factor, and RhoG, toward activation of Rac1 (21)(22)(23)(24). However, the functional roles of Dock4 in the central nervous system are only beginning to be understood (25)(26)(27). The detailed molecular mechanism on how Dock4 controls neuronal development and whether the disruption of Dock4 activity is associated with brain dysfunction still remain unclear.…”

<i>Drosophila</i> DOCK Family Protein Sponge Regulates the JNK Pathway during Thorax Development

“…In Drosophila, Mbc regulates myoblast fusion and development of embryonic CNS by binding to ELMO protein to activate Rac1 that plays a role in regulation of the actin cytoskeleton. Spg plays a role in embryonic CNS development via binding to the ELMO protein (Biersmith et al, 2011). The phenotype of the Rac1 mutant is similar to those of the Mbc and spg mutants in embryonic CNS development (Obara et al, 2007), although spg is not involved in embryonic myoblast fusion (Biersmith et al, 2011).…”

“…Myoblast city (Mbc), Sponge (Spg)/CG31048, Zizimin-related (Zir)/CG11376 and Zizimin (Ziz)/ CG42533 belong to DOCK-A, -B, -C and -D subfamilies, respectively (Rushton et al, 1995;Erickson et al, 1997;Meller et al, 2005;Biersmith et al, 2011;Sampson et al, 2012). It is reported that Mbc, a DOCK-A subfamily, appears to have a function similar to that of mammalian DOCK1 and is involved in myoblast fusion (Erickson et al, 1997;Bour et al, 2000).…”

“…Spg is a member of the DOCK-B subfamily in Drosophila. Recent studies have shown that Spg is involved in embryonic central nervous system (CNS) development (Biersmith et al, 2011) and differentiation of R7 photoreceptor cells (Eguchi et al, 2013). Zir is a member of the DOCK-C subfamily in Drosophila involving a proper cellular immune response (Sampson et al, 2012).…”

<i>Drosophila</i> DOCK Family Protein Zizimin Involves in Pigment Cell Differentiation in Pupal Retinae

“…In contrast, during thorax development, Spg positively regulates JNK pathway and this regulation is mediated by its association with Rac1 (Morishita et al, 2014). Spg also regulates development of the central nervous system (CNS) with ELMO during embryogenesis (Biersmith et al, 2011). Other studies reported that in Zir mutants, lamellocytes, a haemocyte subtype in Drosophila fail to encapsulate the parasites and macrophage-like plasmatocytes exhibit a reduced ability in phogocytosis of the infected bacteria (Sampson et al, 2012).…”