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The Journal of Neuroscience, April 25, 2007, 27(17):4725-4736; doi:10.1523/JNEUROSCI.5633-06.2007

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Development/Plasticity/Repair
The Novel GTPase Rit Differentially Regulates Axonal and Dendritic Growth

Pamela J. Lein,^1,2 Xin Guo,² Geng-Xian Shi,³ Melissa Moholt-Siebert,¹ Donald Bruun,¹ and Douglas A. Andres³

¹Center for Research on Occupational and Environmental Toxicology, Oregon Health & Science University, Portland, Oregon 97239, ²Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland 21205, and ³Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky 40536

Correspondence should be addressed to Dr. Pamela Lein, Center for Research on Occupational and Environmental Toxicology/L606, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: leinp{at}ohsu.edu

The Rit GTPase is widely expressed in developing and adult nervous systems, and our previous data with pheochromocytoma cells implicate Rit signaling in NGF-induced neurite outgrowth. In this study, we investigated a role for Rit in neuronal morphogenesis. Expression of a dominant-negative (dn) Rit mutant in hippocampal neurons inhibited axonal growth but potentiated dendritic growth. Conversely, a constitutively active (ca) Rit mutant promoted axonal growth but inhibited dendritic growth. Dendritogenesis is regulated differently in sympathetic neurons versus hippocampal neurons in that sympathetic neurons require NGF and bone morphogenetic proteins (BMPs) to trigger dendritic growth. Despite these differences, dnRit potentiated and caRit blocked BMP7-induced dendritic growth in sympathetic neurons. Biochemical studies indicated that BMP7 treatments that caused dendritic growth also decreased Rit GTP loading. Additional studies demonstrate that caRit increased extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation and pharmacological inhibition of MEK1 (mitogen-activated protein kinase/ERK 1) blocked the axon-promoting and dendrite-inhibiting effects of caRit. These observations suggest that Rit is a convergence point for multiple signaling pathways and it functions to promote axonal growth but inhibit dendritic growth via activation of ERK1/2. Modulation of the activational status of Rit may therefore represent a generalized mechanism across divergent neuronal cell types for regulating axonal versus dendritic growth modes.

Key words: Rit; GTPase; axon; dendrite; ERK; sympathetic neuron; hippocampal neuron; BMP; NGF

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Received Sept. 8, 2006; revised March 19, 2007; accepted March 20, 2007.

Correspondence should be addressed to Dr. Pamela Lein, Center for Research on Occupational and Environmental Toxicology/L606, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97239. Email: leinp{at}ohsu.edu

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