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EphA4-Dependent Axon Guidance Is Mediated by the RacGAP α2-Chimaerin
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Genetics.
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2007 (English)In: Neuron, ISSN 0896-6273, E-ISSN 1097-4199, Vol. 55, no 5, 756-767 p.Article in journal (Refereed) Published
Abstract [en]

Neuronal network formation in the developing nervous system is dependent on the accurate navigation of nerve cell axons and dendrites, which is controlled by attractive and repulsive guidance cues. Ephrins and their cognate Eph receptors mediate many repulsive axonal guidance decisions by intercellular interactions resulting in growth cone collapse and axon retraction of the Eph-presenting neuron. We show that the Rac-specific GTPase-activating protein α2-chimaerin binds activated EphA4 and mediates EphA4-triggered axonal growth cone collapse. α-Chimaerin mutant mice display a phenotype similar to that of EphA4 mutant mice, including aberrant midline axon guidance and defective spinal cord central pattern generator activity. Our results reveal an α-chimaerin-dependent signaling pathway downstream of EphA4, which is essential for axon guidance decisions and neuronal circuit formation in vivo.

Place, publisher, year, edition, pages
2007. Vol. 55, no 5, 756-767 p.
Keyword [en]
Animals, Animals; Newborn, Brain/abnormalities/metabolism/physiopathology, Cell Communication/genetics, Cell Differentiation/*genetics, Cells; Cultured, Central Nervous System/*abnormalities/cytology/*metabolism, Chimerin 1/genetics/*metabolism, Down-Regulation/genetics, Gait Disorders; Neurologic/genetics/metabolism/physiopathology, Gene Expression Regulation; Developmental/genetics, Growth Cones/*metabolism/ultrastructure, Mice, Mice; Knockout, Neural Pathways/abnormalities/metabolism/physiopathology, Protein Binding/genetics, Pyramidal Tracts/abnormalities/metabolism/physiopathology, Receptor; EphA4/*metabolism, Signal Transduction/genetics, Spinal Cord/abnormalities/cytology/metabolism
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-14467DOI: 10.1016/j.neuron.2007.07.038ISI: 000249857000011PubMedID: 17785182OAI: oai:DiVA.org:uu-14467DiVA: diva2:42237
Available from: 2008-01-30 Created: 2008-01-30 Last updated: 2011-01-26Bibliographically approved
In thesis
1. Spinal Control of Locomotion: Developmental and Functional Aspects
Open this publication in new window or tab >>Spinal Control of Locomotion: Developmental and Functional Aspects
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Neuronal networks are the central functional units of the nervous system. Knowledge about the identity of participating neurons and the assembly of these during development is crucial for the understanding of CNS function. A promising system to dissect the development and functionalities of a neuronal network is the central pattern generator (CPG) for locomotion. We used screening approaches to identify spinal neuronal subpopulations by their specific gene expression, potentially involved in CPG function. Amongst others we found paired-like homeodomain transcription factor 2 (Pitx2) as a cholinergic interneuron marker for partition cells, with a possible role in the spinal network for locomotion. In addition, we present two genes, Chondrolectin (Chodl) and Estrogen-related receptor beta (ERRβ) as novel markers for fast and slow motor neurons, respectively.

The neuronal components of the CPG integrate three key functions; rhythm generation, ipsilateral flexors/extensors coordination and bilateral coordination over the midline. Commissural interneurons (CINs) are considered to participate in the latter. During development axons are guided to their targets by the help of axon guidance molecules. Netrin-1 and its receptor DCC (Deleted in Colorectal Cancer) have been shown to play an important role for spinal cord neurons in axon-pathfinding and migration towards the midline. We show that loss of netrin-1 functionally results in a switch from alternating to synchronous left-right locomotor activity and deletion of DCC surprisingly leads to a different phenotype, best described as uncoordination. Thus, during development, netrin-1 and DCC play a critical role for the establishment of a functional balanced CPG. Further we show a selective loss of CINs, predominantly from dorsally originating subtypes, not affecting the ventral-most V3 subtype in netrin-1 mutant mice, but a loss of CINs from all progenitor domains in Dcc mutant mice. Together, our data suggest a netrin-1-independent mechanism for DCC in axon guidance and a role of the most ventral originating CINs as part of the neuronal network controlling synchronous activities over the midline.

Another pair of axon guidance molecules, EphA4 and ephrinB3, has been shown to cooperate in preventing ipsilateral interneurons from crossing the spinal midline and if either molecule is deleted in mice, this will result in a defect in left-right coordination of locomotion. We provide in vivo and in vitro evidence that the GTPase-activating protein α2-chimerin, as a downstream molecule of EphA4 signaling, is essential in axon guidance decisions involved in the correct formation of the spinal circuitry for locomotion.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 40 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 514
neuronal network, commissural interneuron, developmental interneuron subtypes, V3, mouse genetics, Pitx2, axon guidance, netrin-1, DCC, EphA4
National Category
Research subject
Neuroscience; Developmental Neurosciences; Molecular Genetics
urn:nbn:se:uu:diva-112472 (URN)978-91-554-7704-2 (ISBN)
Public defence
2010-02-26, B42, BMC, Husargatan 3, Uppsala, 09:15 (English)
Available from: 2010-02-05 Created: 2010-01-13 Last updated: 2010-02-05Bibliographically approved

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