We seek to answer two questions: how do neurons become connected during development, and why do they become disconnected during neurodegenerative disease? The mechanisms responsible for growth of axons along the longitudinal axis of the central nervous system (CNS) have been mysterious in both vertebrates and invertebrates. This is a crucial question for metazoan neural development, and is also the essential process for repair of catastrophic spinal cord injuries. In light of results we have obtained over the past year, we can now largely account for how this process occurs in the Drosophila central nervous system. First, we have disentangled the mechanism by which the development of four different CNS cell types are coordinated to produce a track along which longitudinal axons can grow between successive segments. This involves spreading a thin layer of neuronal tissue along the surfaces of specialized glial cells, and shaping that layer into a continuous adhesive band that bridges between segments. Second, we have determined what drives growing axons to extend along that track. A receptor on the surface of the growing axon, Notch, suppresses the activity of a major cytoplasmic signaling protein, the Abl tyrosine kinase. This promotes the formation of long filopodia by the growing axons, and suppresses the adhesion of those axons to their substratum. Together, these effects establish a balance among the steps in the cycle of dynamics of the cytoskeleton that is conducive to growth. The view that axon guidance molecules achieve their effects by producing a particular balance in the dynamics of cytoskeleton organization, and not by explicit growth-promoting and growth-retarding activities, is a novel hypothesis that brings into focus a large body of data on neural wiring that has until now been contradictory and confusing. We argue that this alternate perspective will greatly advance our understanding of the mechanisms of neural wiring, and also of cell motility. In the course of this work we have been forced to dissect the signaling network defined by the Abl protein tyrosine kinase. Abl was the first cellular proto-oncogene found to be responsible for a major human cancer. Central components of its signaling pathway have been known for many years, but how they combine to form a pathway has resisted analysis. We found that by analyzing Abl function in epithelia we could order the steps in this signaling pathway. We found, first, that the Disabled protein, long thought to be an effector of Abl, is actually an upstream regulator that localizes the kinase. Moreover, preliminary results suggest that rather than being a single, linear pathway, the Abl signaling system has two branches that are largely separate, though coordinated. This likely accounts for many of the ambiguities and complexities in prior studies of this pathway. Unraveling the mechanism of Abl signaling is central to understanding the regulation and machinery of nerve growth, and also for treatment of hematopoietic malignancies such as chronic myelogenous leukemia.

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Kannan, Ramakrishnan; Cox, Eric; Wang, Lei et al. (2018) Tyrosine phosphorylation and proteolytic cleavage of Notch are required for non-canonical Notch/Abl signaling in Drosophila axon guidance. Development 145:
Kannan, Ramakrishnan; Giniger, Edward (2017) New perspectives on the roles of Abl tyrosine kinase in axon patterning. Fly (Austin) 11:260-270
Kannan, Ramakrishnan; Song, Jeong-Kuen; Karpova, Tatiana et al. (2017) The Abl pathway bifurcates to balance Enabled and Rac signaling in axon patterning in Drosophila. Development 144:487-498
Kannan, Ramakrishnan; Kuzina, Irina; Wincovitch, Stephen et al. (2014) The Abl/enabled signaling pathway regulates Golgi architecture in Drosophila photoreceptor neurons. Mol Biol Cell 25:2993-3005
Ferreira, Tiago; Ou, Yimiao; Li, Sally et al. (2014) Dendrite architecture organized by transcriptional control of the F-actin nucleator Spire. Development 141:650-60
Kotlyanskaya, Lucy; McLinden, Kristina A; Giniger, Edward (2013) Of proneurotrophins and their antineurotrophic effects. Sci Signal 6:pe6
Giniger, Edward (2012) Notch signaling and neural connectivity. Curr Opin Genet Dev 22:339-46
Shivalkar, Madhuri; Giniger, Edward (2012) Control of dendritic morphogenesis by Trio in Drosophila melanogaster. PLoS One 7:e33737
Song, Jeong K; Giniger, Edward (2011) Noncanonical Notch function in motor axon guidance is mediated by Rac GTPase and the GEF1 domain of Trio. Dev Dyn 240:324-32
Gates, Michael A; Kannan, Ramakrishnan; Giniger, Edward (2011) A genome-wide analysis reveals that the Drosophila transcription factor Lola promotes axon growth in part by suppressing expression of the actin nucleation factor Spire. Neural Dev 6:37

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