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G₁₂/G₁₃ Deficiency Causes Localized Overmigration of Neurons in the Developing Cerebral and Cerebellar Cortices

Alexandra Moers,^1, Alexander Nürnberg,^1, Sandra Goebbels,² Nina Wettschureck,¹ and Stefan Offermanns^1*

Institute of Pharmacology, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany,¹ Max-Planck-Institute of Experimental Medicine, Goettingen, Germany²

Received 13 April 2007/ Returned for modification 25 May 2007/ Accepted 26 November 2007

The heterotrimeric G proteins G₁₂ and G₁₃ link G-protein-coupled receptors to the regulation of the actin cytoskeleton and the induction of actomyosin-based cellular contractility. Here we show that conditional ablation of the genes encoding the -subunits of G₁₂ and G₁₃ in the nervous system results in neuronal ectopia of the cerebral and cerebellar cortices due to overmigration of cortical plate neurons and cerebellar Purkinje cells, respectively. The organization of the radial glia and the basal lamina was not disturbed, and the Cajal-Retzius cell layer had formed normally in mutant mice. Embryonic cortical neurons lacking G₁₂/G₁₃ were unable to retract their neurites in response to lysophosphatidic acid and sphingosine-1-phosphate, indicating that they had lost the ability to respond to repulsive mediators acting via G-protein-coupled receptors. Our data indicate that G₁₂/G₁₃-coupled receptors mediate stop signals and are required for the proper positioning of migrating cortical plate neurons and Purkinje cells during development.

Published ahead of print on 17 December 2007.

These authors contributed equally.

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