We seek to answer two questions: how do neurons become connected during development, and why do they become disconnected during neurodegenerative disease? 

 Most of our effort on axon growth and guidance currently focuses on understanding the action of the signaling modules that translate receptor signals at the growth cone surface into guided motility of the axon tip. We focus in particular on the Abl tyrosine kinase signaling pathway, which plays a central role downstream of many of the most common, phylogenetically-conserved guidance receptors. In a completely unexpected twist, in the past year we discovered that the guidance function of Abl is executed, in part, through regulation of the secretory apparatus. Thus, we have made the following discoveries: 1. The key Abl effector, the actin-regulatory protein Enabled, is selectively associated with the cis-Golgi compartment in developing Drosophila photoreceptor neurons. We have shown this by standard fluorescence microscopy, super-resolution fluorescence and by immunoelectron microscopy. 2. Loss-of function of Abl kinase, or gain-of-function of its antagonist Enabled, cause fragmentation of the Golgi apparatus, and relocalization of Golgi cisternae within the cell bodies of photoreceptor neurons. Live imaging demonstrates that reducing Abl activity increases the frequency of splitting of Golgi cisternae, and decreases the frequency of fusions. 3. Genetic and pharmacological experiments demonstrate that the effect of Abl on the Golgi structure and distribution is mediated through Abl-dependent regulation of the actin cytoskeleton. 4. Two lines of evidence suggest that the effect of Abl pathway mutations on axon guidance are mediated, in part, by their effects on secretion. First, mutations that interfere directly with Golgi function produce axonal defects that mimic those of Abl mutants. Second, genetic tests show that bona fide secretory mutants act downstream of Abl kinase in the pathway leading to axon patterning. Together, these data strongly suggest that the axonal phenotypes of Abl mutants are due, in part, to modulation of the secretory apparatus by Abl, working through the Abl-dependent regulation of actin structure and dynamics. Abl is a central regulator of axon patterning, cell polarity and epithelial organization and integrity in both vertebrates and invertebrates. It is the causative oncogene for two common forms of human leukemia, and recent evidence suggest it has a critical role in the etiology of Parkinsons disease. For three decades, studies of Abl have focused on its effects on the cortical actin cytoskeleton. Our results suggest that a vast body of work on Abl must now be reconsidered to ascertain how many of its effects are actually mediated, in part or in whole, through its effects on protein sorting, trafficking and secretion.

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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
Shivalkar, Madhuri; Giniger, Edward (2012) Control of dendritic morphogenesis by Trio in Drosophila melanogaster. PLoS One 7:e33737
Trunova, Svetlana; Baek, Brian; Giniger, Edward (2011) Cdk5 regulates the size of an axon initial segment-like compartment in mushroom body neurons of the Drosophila central brain. J Neurosci 31:10451-62
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
Kuzina, Irina; Song, Jeong K; Giniger, Edward (2011) How Notch establishes longitudinal axon connections between successive segments of the Drosophila CNS. Development 138:1839-49
Song, Jeong K; Kannan, Ramakrishnan; Merdes, Gunter et al. (2010) Disabled is a bona fide component of the Abl signaling network. Development 137:3719-27