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The Journal of Neuroscience, July 15, 2001, 21(14):5191-5202

2-Chimaerin, a Cdc42/Rac1 Regulator, Is Selectively Expressed in the Rat Embryonic Nervous System and Is Involved in Neuritogenesis in N1E-115 Neuroblastoma Cells

Christine Hall¹, Gregory J. Michael^{1, 2}, Nansi Cann^{1, 2}, Giovanna Ferrari^{1, 2}, Mabel Teo^{1, 2}, Tom Jacobs¹, Clinton Monfries^{1, 2}, and Louis Lim^{1, 2}

¹ Department of Neurochemistry, Institute of Neurology, University College London, London WC1N 1PJ, United Kingdom, and ² Glaxo/IMCB Group, Institute of Molecular and Cell Biology, National University of Singapore, Singapore 117609

Neuronal differentiation involves Rac and Cdc42 GTPases. -Chimaerin, a Rac/Cdc42 regulator, occurs as 1- and alternatively spliced Src homology 2 (SH2) domain-containing 2-isoforms. 2-chimaerin mRNA was highly expressed in the rat embryonic nervous system, especially in early postmitotic neurons. 1-chimaerin mRNA was undetectable before embryonic day 16.5. Adult 2-chimaerin mRNA was restricted to neurons within specific brain regions, with highest expression in the entorhinal cortex. 2-chimaerin protein localized to neuronal perikarya, dendrites, and axons. The overall pattern of 2-chimaerin mRNA expression resembles that of cyclin-dependent kinase regulator p35 (CDK5/p35) which participates in neuronal differentiation and with which chimaerin interacts. To determine whether 2-chimaerin may have a role in neuronal differentiation and the relevance of the SH2 domain, the morphological effects of both chimaerin isoforms were investigated in N1E-115 neuroblastoma cells. When plated on poly-lysine, transient 2-chimaerin but not 1-chimaerin transfectants formed neurites. Permanent 2-chimaerin transfectants generated neurites whether or not they were stimulated by serum starvation, and many cells were enlarged. Permanent 1-chimaerin transfectants displayed numerous microspikes and contained F-actin clusters, a Cdc42-phenotype, but generated few neurites. In neuroblastoma cells, 2-chimaerin was predominantly soluble with some being membrane-associated, whereas 1-chimaerin was absent from the cytosol, being membrane- and cytoskeleton-associated, paralleling their subcellular distribution in brain. Transient transfection with 2-chimaerin mutated in the SH2 domain (N94H) generated an 1-chimaerin-like phenotype, protein partitioned in the particulate fraction, and in NGF-stimulated pheochromocytoma cell line 12 (PC12) cells, neurite formation was inhibited. These results indicate a role for 2-chimaerin in morphological differentiation for which its SH2 domain is vital.

Key words: 2-chimaerin; Rac; Cdc42; GTPase; GAP; SH2; neurite outgrowth; embryonic brain; N1E-115 neuroblastoma; PC12; cdk5/p35; Crmp

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21145191-12$05.00/0

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