P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination

Abstract

The small GTPase Rac controls cell morphology, gene expression, and reactive oxygen species formation. Manipulations of Rac activity levels in the cerebellum result in motor coordination defects, but activators of Rac in the cerebellum are unknown. P-Rex family guanine-nucleotide exchange factors activate Rac. We show here that, whereas P-Rex1 expression within the brain is widespread, P-Rex2 is specifically expressed in the Purkinje neurons of the cerebellum. We have generated P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /PRex2 ؊/؊ mice, analyzed their Purkinje cell morphology, and assessed their motor functions in behavior tests. The main dendrite is thinned in Purkinje cells of P-Rex2 ؊/؊ pups and dendrite structure appears disordered in Purkinje cells of adult P-Rex2 ؊/؊ and P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice. P-Rex2 ؊/؊ mice show a mild motor coordination defect that progressively worsens with age and is more pronounced in females than in males. P-Rex1 ؊/؊ /P-Rex2 ؊/؊ mice are ataxic, with reduced basic motor activity and abnormal posture and gait, as well as impaired motor coordination even at a young age. We conclude that P-Rex1 and P-Rex2 are important regulators of Purkinje cell morphology and cerebellar function.G protein-coupled receptor ͉ guanine-nucleotide exchange factor ͉ phosphoinositide-3-kinase ͉ small GTPase Rac ͉ ataxia T he small GTPase Rac (isoforms 1, 2, and 3) controls the structure of the actomyosin cytoskeleton, gene expression, and reactive oxygen species (ROS) formation (1). In the nervous system, Rac is essential for all stages of neuronal development (neurite, axon, and dendrite formation, axon pathfinding, dendrite branching and dendritic spine formation, and survival), as shown by manipulations of Rac activity in the nervous system of animals, neuronal cell lines, and primary cultures (2).Deletion of the ubiquitous Rac1 from the mouse, whether total or specifically in the brain, is embryonic lethal (3, 4), but transgenic overexpression of constitutively active Rac1 in the Purkinje neurons of the cerebellum results in severe ataxia, with animals unable to walk in a straight line and poor performance on the rotarod (5). Similarly, deletion of nervous system-specific Rac3 results in an increased ability for learning and coordination of skilled movements (6), deletion of the Rac-GAP ␣-Chimerin induces a hopping gait due to misguidance of corticospinal tract axons (7), and deletion of the brain-specific form of the Rac-effector Wave, which links Rac to the actin cytoskeleton, causes defects in motor coordination, learning, and memory (8).Like all small GTPases, Rac is activated by guanine-nucleotide exchange factors (GEFs) (9). Several Rac-GEFs are known to control neuronal development: Tiam1/Stef regulates neurite and axon outgrowth and dendritic spine formation (2, 10); Vav2 and Vav3 control axon outgrowth from retina to thalamus (11); Trio governs neurite outgrowth, axon extension, and pathfinding (2); Kalirin regulates neurite and axon outgrowth and dendritic spine formation (2); Dock180 controls neurite ou...

P-Rex1 and Vav1 Cooperate in the Regulation of Formyl-Methionyl-Leucyl-Phenylalanine–Dependent Neutrophil Responses

“…In this project, we assessed the roles of the P-Rex and Vav families in GPCR-dependent neutrophil function to determine potential redundancy or cooperation between them. Previous studies have shown that, of the P-Rex family, PRex1 is highly expressed in neutrophils, whereas P-Rex2 expression is undetectable, suggesting that P-Rex1 is the only P-Rex family member in these cells (22,31). All three Vav isoforms are expressed, however Vav2 is 30-fold less abundant than Vav1 and 120-fold less abundant than Vav3 (25); hence, Vav1 and Vav3 are the major isoforms in mouse neutrophils.…”

Molecular Pathways: P-Rex in Cancer

“…Physiologic relevance of P-Rex proteins P-Rex1 is mainly expressed in peripheral blood leukocytes and in the brain and is also expressed in several other tissues (8,(11)(12)(13)(14). P-Rex2 is widely expressed and is strongly present in skeletal muscle, the small intestine, heart, lung, and placenta, being absent from peripheral blood leukocytes (10,11,13).…”

“…P-Rex2 is widely expressed and is strongly present in skeletal muscle, the small intestine, heart, lung, and placenta, being absent from peripheral blood leukocytes (10,11,13). P-Rex1 À/À mice are viable and apparently healthy but have mild neutrophilia (15).…”

Upregulation of PREX2 promotes the proliferation and migration of hepatocellular carcinoma cells via PTEN-AKT signaling

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