Involvement of a Rac activator,P-Rex1, in neurotrophin-derived signaling and neuronal migration.
Rho-family GTPases play key roles in regulating cytoskeletal reorganization, contributing to many aspects of nervous system development. Their activities are known to be regulated by guanine nucleotide exchange factors (GEFs), in response to various extracellular cues. P-Rex1, a GEF for Rac, has been mainly investigated in neutrophils, in which this molecule contributes to reactive oxygen species formation. However, its role in the nervous system is essentially unknown. Here we describe the expression profile and a physiological function of P-Rex1 in nervous system development. In situ hybridization revealed that P-Rex1 is dynamically expressed in a variety of cells in the developing mouse brain, including some cortical and DRG neurons. In migrating neurons in the intermediate zone, P-Rex1 protein was found to localize in the leading process and adjacent cytoplasmic region. When transfected in pheochromocytoma PC12 cells, P-Rex1 can be activated by NGF, causing an increase in GTP-bound Rac1 and cell motility. Deletion analyses suggested roles for distinct domains of this molecule. Experiments using a P-Rex1 mutant lacking the Dbl-homology domain, a dominant-negative-like form, and small interfering RNA showed that endogenous P-Rex1 was involved in cell migration of PC12 cells and primary cultured neurons from the embryonic day 14 cerebral cortices, induced by extracellular stimuli (NGF, BDNF, and epidermal growth factor). Furthermore, in utero electroporation of the mutant protein into the embryonic cerebral cortex perturbed radial neuronal migration. These findings suggest that P-Rex1, which is expressed in a variety of cell types, is activated by extracellular cues such as neurotrophins and contributes to neuronal migration in the developing nervous system.
Yoshizawa
Masato
M
Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Kawauchi
Takeshi
T
Sone
Masaki
M
Nishimura
Yoshiaki V
YV
Terao
Mami
M
Chihama
Kaori
K
Nabeshima
Yo-ichi
Y
Hoshino
Mikio
M
D000199:Actins / Q000378:metabolism; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000196:embryology / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005455:Fluorescent Antibody Technique / Q000379:methods; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D051379:Mice; D008813:Mice, Inbred ICR; D016296:Mutagenesis / Q000502:physiology; D020932:Nerve Growth Factor / Q000494:pharmacology; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D020744:rac GTP-Binding Proteins / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; D020662:Guanine Nucleotide Exchange Factors; D009414:Nerve Growth Factors; C453280:PREX1 protein, human; D049452:Green Fluorescent Proteins; D020932:Nerve Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D020813:Receptor, trkB; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins