Dscam1 Forms a Complex with Robo1 and the N-Terminal Fragment of Slit to Promote the Growth of Longitudinal Axons.

The Slit protein is a major midline repellent for central nervous system (CNS) axons. In vivo, Slit is proteolytically cleaved into N- and C-terminal fragments, but the biological significance of this is unknown. Analysis in the Drosophila ventral nerve cord of a slit allele (slit-UC) that cannot be cleaved revealed that midline repulsion is still present but longitudinal axon guidance is disrupted, particularly across segment boundaries. Double mutants for the Slit receptors Dscam1 and robo1 strongly resemble the slit-UC phenotype, suggesting they cooperate in longitudinal axon guidance, and through biochemical approaches, we found that Dscam1 and Robo1 form a complex dependent on Slit-N. In contrast, Robo1 binding alone shows a preference for full-length Slit, whereas Dscam1 only binds Slit-N. Using a variety of transgenes, we demonstrated that Dscam1 appears to modify the output of Robo/Slit complexes so that signaling is no longer repulsive. Our data suggest that the complex is promoting longitudinal axon growth across the segment boundary. The ability of Dscam1 to modify the output of other receptors in a ligand-dependent fashion may be a general principle for Dscam proteins.

Unraveling cis-regulatory mechanisms at the abdominal-A and Abdominal-B genes in the Drosophila bithorax complex.

Genome sequencing has revealed that in metazoans, only a small percentage of DNA actually codes for functional proteins. Research efforts have focused on elucidating the purpose of the rest of the genome, which was initially largely thought of as mere 'junk' DNA. One genomic region that is proving to be a rich source of new information is the Drosophila bithorax complex (BX-C). At this homeotic gene complex, many different classes of cis-regulatory elements, such as insulators, silencers, enhancers, and promoters, work together to tightly control gene expression during development. Recent studies have begun to unravel the intricate nature of these regulatory interactions. The BX-C was first discovered and characterized by Ed Lewis over three decades ago. In his seminal 1978 Nature paper, Lewis speculated that "substances" originating from the nongenic regions of the BX-C may regulate expression of the neighboring abdominal-A and Abdominal-B homeotic genes. A number of discoveries in the last few years suggest that he was right. The activation of some of the cis-sequences at the complex appears to be controlled by nongenic transcription, providing a further level of regulatory complexity to regions of nonprotein coding DNA. The hope is that these studies of gene regulation at the BX-C in the humble fruit fly will provide clues as to how vast intergenic regions contribute to the incredible complexity of gene regulation in other species, including humans.