Abstract
The Rho family of small GTPases controls a wide range of cellular processes in eukaryotic cells, such as normal cell growth, proliferation, differentiation, gene regulation, actin cytoskeletal organization, cell fate determination, and neurite outgrowth. The activation of Rho-GTPases requires the exchange of GDP for GTP, a process catalyzed by the Dbl family of guanine nucleotide exchange factors. We demonstrate that a newly identified guanine nucleotide exchange factor, GEFT, is widely expressed in the brain and highly concentrated in the hippocampus, and the Purkinje and granular cells of the cerebellum. Exogenous expression of GEFT promotes dendrite outgrowth in hippocampal neurons, resulting in spines with larger size as compared with control spines. In neuroblastoma cells, GEFT promotes the active GTP-bound state of Rac1, Cdc42, and RhoA and increases neurite outgrowth primarily via Rac1. Furthermore, we demonstrated that PAK1 and PAK5, both downstream effectors of Rac1/Cdc42, are necessary for GEFT-induced neurite outgrowth. AP-1 and NF-kappaB, two transcriptional factors involved in neurite outgrowth and survival, were up-regulated in GEFT-expressing cells. Together, our data suggest that GEFT enhances dendritic spine formation and neurite outgrowth in primary neurons and neuroblastoma cells, respectively, through the activation of Rac/Cdc42-PAK signaling pathways.
Highlights
Neurite outgrowth, a process responsible for neuronal patterning and connections, is crucial for the development of the nervous system [1]
Using primary hippocampal neurons and Neuro2a (N2A) neuroblastoma cell lines, we examined the role that GEFT plays in the regulation of dendritic spine morphogenesis and neurite outgrowth
GEFT Is Highly Expressed in the Hippocampus, Granular Layer, and Purkinje Cells of the Adult Mouse Brain—To investigate the potential role of GEFT in neuronal cells and in brain development, we examined the expression of GEFT transcript using in situ hybridization on brain sections of adult mice
Summary
A process responsible for neuronal patterning and connections, is crucial for the development of the nervous system [1]. The Rho family of small GTPases, which comprises the key regulators of the actin cytoskeleton [3], has been shown to mediate the morphological changes that are observed during neuronal development and plasticity such as neurite outgrowth, axonal guidance, and dendrite topology modifications (4 –9). Pleckstrin homology domains promote the translocation of Dbl-related proteins to plasma membranes [19, 20], as well as participate directly in GTPase binding and regulation of GEF activity [21]. Expression of GEFT has been shown to promote the formation of lamellipodia, actin microspikes, and filopodia in NIH3T3 cells via activation of the Rho family of small GTPases [22]. Using primary hippocampal neurons and Neuro2a (N2A) neuroblastoma cell lines, we examined the role that GEFT plays in the regulation of dendritic spine morphogenesis and neurite outgrowth. We studied the molecular signaling mechanisms by which GEFT regulates dendritic spine morphogenesis and neurite outgrowth
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