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The Journal of Neuroscience, September 29, 2004, 24(39):8510-8521; doi:10.1523/JNEUROSCI.1264-04.2004

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Development/Plasticity/Repair
Abl Tyrosine Kinase Promotes Dendrogenesis by Inducing Actin Cytoskeletal Rearrangements in Cooperation with Rho Family Small GTPases in Hippocampal Neurons

Shiloh B. Jones, Hope Y. Lu, and Qun Lu

Department of Anatomy and Cell Biology, The Brody School of Medicine at East Carolina University, Greenville, North Carolina 27858

Nonreceptor tyrosine kinase Abl is an actin-binding protein and a key regulator of neuronal axonal development. Although Abl family kinases also are localized in dendrites and are implicated in postsynaptic functions, it is not clear how Abl kinases regulate dendritic morphogenesis. Using a developing hippocampal culture as a model, we found that the inhibition of Abl kinases by STI571 leads to a remarkable simplification of dendritic branching similar to the phenotype caused by an increased activity of small GTPase RhoA. Time-lapse microscopic imaging reveals a prominent reduction of dendritic branching. In contrast, neurons expressing a constitutively active v-abl construct (CA-Abl) show an exuberant microtubule-associated protein 2-positive (MAP2-positive) dendrite outgrowth, suggesting that Abl modulates dendritic growth. Biochemical assays using a glutathione S-transferase pull-down method to determine GTP-bound active Rho GTPases demonstrate that Abl inhibition increases RhoA activity but has no effect on the activity of Rac1 or Cdc42. At the cellular level the alteration of Abl also changes actin organization consistent with RhoA inhibition. Suppression of the RhoA downstream effector Rho kinase reverses STI571-induced dendritic simplification, demonstrating that activity of the Rho pathway is responsible for the Abl-induced changes in dendrogenesis. Furthermore, CA-Abl-induced neurite outgrowth is blocked by the expression of a constitutively active RhoA construct. The CA-Abl phenotype is not affected by destabilization of microtubules but is reversed partially when actin filaments are stabilized with jasplakinolide. Together, these studies support a critical role for Abl kinases in regulating dendrogenesis by inducing actin cytoskeletal rearrangements in cooperation with Rho GTPases.

Key words: nonreceptor tyrosine kinase; neuronal morphogenesis; Rho/Rac/Cdc42; actin cytoskeleton; Rho kinase; STI571/Gleevec/imatinib mesylate

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Received April 3, 2004; revised July 2, 2004; accepted July 28, 2004.

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