Control of Dendritic Morphogenesis by Trio in Drosophila melanogaster

Abl tyrosine kinase and its effectors among the Rho family of GTPases each act to control dendritic morphogenesis in Drosophila. It has not been established, however, which of the many GTPase regulators in the cell link these signaling molecules in the dendrite. In axons, the bifunctional guanine exchange factor, Trio, is an essential link between the Abl tyrosine kinase signaling pathway and Rho GTPases, particularly Rac, allowing these systems to act coordinately to control actin organization. In dendritic morphogenesis, however, Abl and Rac have contrary rather than reinforcing effects, raising the question of whether Trio is involved, and if so, whether it acts through Rac, Rho or both. We now find that Trio is expressed in sensory neurons of the Drosophila embryo and regulates their dendritic arborization. trio mutants display a reduction in dendritic branching and increase in average branch length, whereas over-expression of trio has the opposite effect. We further show that it is the Rac GEF domain of Trio, and not its Rho GEF domain that is primarily responsible for the dendritic function of Trio. Thus, Trio shapes the complexity of dendritic arbors and does so in a way that mimics the effects of its target, Rac

Positive feedback between p53 and TRF2 during telomere-damage signalling and cellular senescence

The telomere-capping complex (shelterin) protects functional telomeres from initiating unwanted DNA damage response. Uncapped telomeres at the end of cellular replicative lifespan lose this protective mechanism and trigger DNA damage signaling to activate p53 and thereby induce replicative senescence. Here we identify a signaling pathway involving p53, Siah-1, a p53-inducible E3 ubiquitin ligase, and TRF2, a component of the shelterin complex. Endogenous Siah-1 and TRF2 were up- and down-regulated, respectively, at replicative senescence with activated p53. A series of experimental manipulations of p53 showed that p53 induced Siah-1 and repressed TRF2 protein levels. The p53-dependent ubiquitination and proteasomal degradation of TRF2 were attributed to the E3 ligase activity of Siah-1. Siah-1 knockdown stabilized TRF2 and delayed the onset of cellular replicative senescence, suggesting the role of Siah-1 and TRF2 in p53-regulated senescence. This study reveals that p53, a downstream effector of the telomere-initiated damage signaling, also functions upstream of the shelterin complex