Decreased Mbc and ELMO function exhibit abnormal ommatididal organization in the eye and thorax closure defects in the adult. In addition, loss-of-function studies have Ginsenoside-Ro demonstrated that the Rac genes are required redundantly in a variety of developmental processes, including border cell migration, myoblast fusion, and axon guidance in the developing nervous system. Last, genetic interactions exist between the atypical GEF Mbc-ELMO complex and their target GTPase Rac. A genetic screen in the eye uncovered an allele of mbc that suppresses the Rac1 overexpression phenotype. In support of this, removal of one copy of both Rac1 and Rac2 are capable of ameliorating the ”activated-Rac” phenotype exhibited by co-expression of both Mbc and ELMO in the eye. Although the work cited above provides convincing evidence that the DOCK180/Mbc-ELMO complex is essential in development, the mechanism by which at least five Rac-specific DOCK proteins bind to one or more ELMO proteins in vertebrates to modulate actin regulation in a tissue-specific manner is not clear. DOCK180, DOCK4, and DOCK5 are broadly expressed in many tissues, including the brain and nervous system. In contrast, DOCK2 is expressed specifically in hematopoietic cells, while DOCK3 expression is primarily restricted to the brain and spinal cord. In 3,4,5-Trimethoxyphenylacetic acid addition to their complex expression patterns, DOCK family members exhibit pleiotropic functions in development. DOCK180 has recently been shown to be required for Rac-mediated axon outgrowth in cortical neurons in response to netrin-1, neurite outgrowth as mediated by nerve growth factor, and axon pruning via ephrin-B3. Mouse knock-outs show DOCK180 is required in concert with DOCK5 in muscle fusion. DOCK3 colocalizes with N-cadherin and actin in neuronal differentiation. MOCA is also linked to Alzheimer’s disease, where it accumulates in neurofibrillary tangles and modulates betaamyloid precursor processing. Consistent with this, mice lacking DOCK3 exhibit axonal degeneration. Finally, knockdown of DOCK4 results in reduced dendritic growth and branching in hippocampal neurons. Drosophila provides an excellent system to characterize this conserved pathway with a single ELMO ortholog. Using proteomics approaches for identifying new players in the ELMO-mediated pathway in the developing embryo, we have uncovered Spg, the Drosophila ortholog of human DOCK3/4, as an ELMO-interacting protein. In contrast to the well-established role of Mbc in myoblast fusion, Spg is not required with ELMO in somatic muscle development. However, the two Drosophila DOCK family members Mbc and Spg are required in the developing nerve cord. Moreover, Spg can be recruited to the membrane by Ncadherin in S2 cells, providing a mechanism for Spg localization that may function to mediate the development of axonal pathways. In the musculature, the only known GEF shown to be required for Rac activation is the Mbc-ELMO complex. However, in the developing nervous system, in addition to the unconventional DOCK-ELMO complexes, the conventional GEFs Trio and Sos are required. It is not clear how these multiple GEFs are regulated throughout CNS development. Possible mechanisms include the: regulation of GEF expression either in subsets of specific neurons or precise subcellular localization within the same neuron; unique physical associations between GEFs and receptors specific for distinct steps in axonal patterning; and regulation of GEF activity via post-translational modifications including phosphorylation or ubiquitination. While these ideas have not been examined in detail for all known GEFs, what is known is discussed below. First, it is possible mechanisms exist within the cell or tissue to compartmentalize GEF function as the spatial expression patterns of all GEFs in the developing ventral nerve cord seems to be fairly broad. Mbc is expressed at low or undetectable levels with reagents currently available, while Spg is expressed in all commissural and longitudinal axons, but not glial cells.