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The ephrin/Eph system plays a central role in neuronal circuit formation; however, its downstream effectors are poorly understood. Here we show that alpha-chimerin Rac GTPase-activating protein mediates ephrinB3/EphA4 forward signaling. We discovered a spontaneous mouse mutation, miffy (mfy), which results in a rabbit-like hopping gait, impaired corticospinal axon guidance, and abnormal spinal central pattern generators. Using positional cloning, transgene rescue, and gene targeting, we demonstrated that loss of alpha-chimerin leads to mfy phenotypes similar to those of EphA4(-/-) and ephrinB3(-/-) mice. alpha-chimerin interacts with EphA4 and, in response to ephrinB3/EphA4 signaling, inactivates Rac, which is a positive regulator of process outgrowth. Moreover, downregulation of alpha-chimerin suppresses ephrinB3-induced growth cone collapse in cultured neurons. Our findings indicate that ephrinB3/EphA4 signaling prevents growth cone extension in motor circuit formation via alpha-chimerin-induced inactivation of Rac. They also highlight the role of a Rho family GTPase-activating protein as a key mediator of ephrin/Eph signaling.
Pubmed ID: 17719550
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Database as central repository for both single base nucleotide substitutions and short deletion and insertion polymorphisms. Distinguishes report of how to assay SNP from use of that SNP with individuals and populations. This separation simplifies some issues of data representation. However, these initial reports describing how to assay SNP will often be accompanied by SNP experiments measuring allele occurrence in individuals and populations. Community can contribute to this resource.
View all literature mentionsInternational database for laboratory mouse. Data offered by The Jackson Laboratory includes information on integrated genetic, genomic, and biological data. MGI creates and maintains integrated representation of mouse genetic, genomic, expression, and phenotype data and develops reference data set and consensus data views, synthesizes comparative genomic data between mouse and other mammals, maintains set of links and collaborations with other bioinformatics resources, develops and supports analysis and data submission tools, and provides technical support for database users. Projects contributing to this resource are: Mouse Genome Database (MGD) Project, Gene Expression Database (GXD) Project, Mouse Tumor Biology (MTB) Database Project, Gene Ontology (GO) Project at MGI, and MouseCyc Project at MGI.
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