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Siderovski et al, 1999). The PTB domain recruits RGS12 in a phosphotyrosine-dependent manner to the SNARE-binding region of the Cav2.2 calcium channel (Richman et al, 2005), thereby determining the rate of desensitization of GABAB receptor-mediated calcium current inhibition in dorsal root ganglia (DRG) neurons (Schiff et al, 2000). Little is known about the in vivo function of other domains within mamma- lian RGS12. Recently, we examined RGS12 expression patterns during mouse development. Full-length RGS12 is expressed predominantly in trigeminal and DRG neurons and muscle in the E14.5 embryonic mouse (Martin-McCaffrey et al, 2005), suggesting a role for mammalian RGS12 in myo- and neurogenesis. Loco, the Drosophila RGS12 ortholog, is essential for multiple processes in ?y development, including dorsal/ ventral axis formation, neuroblast asymmetric cell division, and nurse cell dumping (Pathirana et al, 2001;

Yu et al, 2005). loco is expressed in lateral glial cells in the developing embryonic central nervous system and required for correct glial cell differentiation (Granderath et al, 1999). Normal glialCglial cell contacts are absent in loco-de?cient ?ies, resulting in a loss of the bloodCbrain barrier and subsequent gross locomotor defects in surviving mutants. Recently, Loco, the GPCR Moody, and the Ga subunits Gai and Gao were found to be expressed in surface glia;

these four proteins are thought to act as part of a common signaling pathway critical Received:

17 August 2006;

accepted:

27 February 2007;

published online:

22 March

2007 *Corresponding author. Department of Pharmacology, UNC-Chapel Hill School of Medicine,

1106 ME Jones Bldg, CB 7365, Manning Dr Chapel Hill, NC 27599-7365, USA. Tel.: ?

1 919

843 9363;

Fax: ?

1 919

966 5640;

E-mail: [email protected] The EMBO Journal (2007) 26, 2029C2040 | &

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2007 European Molecular Biology Organization The EMBO Journal VOL

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2029 for bloodCbrain barrier formation (Bainton et al, 2005;

Schwabe et al, 2005). The requirement for Loco in glial cell development and normal locomotion suggests that mammalian RGS12 may also play a critical role in glial cell differentiation. Here, we demonstrate that RGS12 facilitates formation of a Ras/ Raf/MEK/ERK multiprotein complex, suggesting a function as a scaffold for the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) cascade. Furthermore, RGS12 interacts with the nerve growth factor (NGF) receptor TrkA,........