P-Rex2 regulates Purkinje cell dendrite morphology and motor coordination.
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(-/-)/P-Rex2(-/-) 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.
Donald
Sarah
S
Inositide Laboratory, Laboratory for Cognitive and Behavioural Neuroscience, Bioinformatics Group, Imaging Facility, and Laboratory for Molecular Neuroscience, The Babraham Institute, Babraham Research Campus, Cambridge CB22 3AT, United Kingdom.
Humby
Trevor
T
Fyfe
Ian
I
Segonds-Pichon
Anne
A
Walker
Simon A
SA
Andrews
Simon R
SR
Coadwell
W John
WJ
Emson
Piers
P
Wilkinson
Lawrence S
LS
Welch
Heidi C E
HC
D000375:Aging / Q000502:physiology; D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism; D003712:Dendrites / Q000378:metabolism*; D005298:Fertility; D020690:GTPase-Activating Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006262:Health; D008168:Lung / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity; D009928:Organ Specificity; D011689:Purkinje Cells / Q000166:cytology* / Q000378:metabolism*
D020690:GTPase-Activating Proteins; C528013:P-Rex2 protein, mouse