The G protein ␤␥-dimer is required for receptor interaction and effector regulation. However, previous approaches have not identified the physiologic roles of individual subtypes in these processes. We used a gene knockout approach to demonstrate a unique role for the G protein ␥ 7 -subunit in mice. Notably, deletion of Gng7 caused behavioral changes that were associated with reductions in the ␣ olf -subunit content and adenylyl cyclase activity of the striatum. These data demonstrate that an individual ␥-subunit contributes to the specificity of a given signaling pathway and controls the formation or stability of a particular G protein heterotrimer.The heterotrimeric G proteins control diverse biological processes by conveying signals from cell-surface receptors to intracellular effectors. Although function was originally ascribed to the GTP-bound ␣-subunit, it is now well established that the ␤␥-dimer plays active roles in the signaling process through upstream recognition of receptors and downstream regulation of effectors (1). Molecular cloning has identified at least 5 ␤-and 12 ␥-subunit genes in the mouse and human genomes. Structurally, ␥-subunits are the most diverse, with four subgroups that show less than 50% identity to each other (2). Moreover, ␥-subunits exhibit very different temporal (3, 4) and spatial (5) patterns of expression. These characteristics suggest that ␥-subunits have heterogeneous functions. However, comparison of their biochemical properties has revealed only modest differences (6 -8), perhaps because of the inherent limitations of transfection and reconstitution approaches. Gene ablation in mice has proven to be a powerful approach to identifying the functional roles of several G protein ␣-subunits (9). We report the first use of a gene targeting strategy to identify a unique function for a member of the ␥-subunit family.The G protein ␥ 7 -subunit (G␥ 7 ) was originally cloned from bovine brain (10). In situ hybridization of rat brain sections revealed that mRNA for G␥ 7 is most highly expressed in the striatum (5), where it is found in 40 -50% of medium sized neurons in the caudate putamen (11). The regional expression of mRNA for G␥ 7 in the brain mirrors that of the striatumenriched D 1 dopamine receptor (D1R), 1 G␣ olf , and adenylyl cyclase Type V (12), suggesting involvement of G␥ 7 in the G␣ olf -mediated stimulation of adenylyl cyclase by dopamine. Single cell RT-PCR analysis confirms that D1R and G␥ 7 are expressed in the same subset of rat neurons (13). Ribozyme suppression studies support a role for G␥ 7 in the endogenous ␤-adrenergic receptor pathway (14) and the heterologously expressed D1R pathway in human embryonic kidney cells (13).

Retinal ganglion cell axons exit the eye, enter the optic stalk, cross the ventral midline at the optic chiasm, and terminate in the optic tectum of the zebrafish. While in the optic stalk, they grow immediately adjacent to cells expressing the powerful retinal axon repellent slit2. The chemokine stromal cell-derived factor-1 (SDF1) is expressed within the optic stalk and its receptor CXCR4 is expressed in retinal ganglion cells. SDF1 makes cultured retinal axons less responsive to slit2. Here, we show that reducing SDF1 signaling in vivo rescues retinal axon pathfinding errors in zebrafish mutants that have a partial functional loss of the slit receptor robo2. In contrast, reducing SDF1 signaling in animals that completely lack the robo2 receptor does not rescue retinal guidance errors. These results demonstrate that endogenous levels of SDF1 antagonize the repellent effects of slit/robo signaling in vivo and that this antagonism is important during axonal pathfinding.