The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration

Kawauchi, Takeshi; Chihama, Kaori; Nabeshima, Yo‐ichi; Hoshino, Mikio

doi:10.1093/emboj/cdg413

Cited by 282 publications

(332 citation statements)

References 51 publications

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“…Although A-class ephrins are not highly expressed in the developing mouse cortex (Yun et al, 2003), it is important to examine the expression of Tiam1 and Ephexin, two exchange factors having opposing effects on the neurites motility, in the cortical region. Furthermore, we also have to consider a homologous protein of Tiam1, STEF, another GEF for Rac1, because STEF is also expressed in the cerebral cortex of developing mice (Matsuo et al, 2002;Kawauchi et al, 2003). We detected the association of the PHnTSS domain Because the PHnTSS region of Tiam1 is highly homologous to the PHnTSS domain of STEF, these Tiam1 fragments may also work as dominant-negative mutants for STEF.…”

Section: Discussionmentioning

confidence: 98%

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

Tanaka

Ohashi

Nakamura

et al. 2004

EMBO J

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Bidirectional signals mediated by Eph receptor tyrosine kinases and their membrane-bound ligands, ephrins, play pivotal roles in the formation of neural networks by induction of both collapse and elongation of neurites. However, the downstream molecular modules to deliver these cues are largely unknown. We report here that the interaction of a Rac1-specific guanine nucleotide-exchanging factor, Tiam1, with ephrin-B1 and EphA2 mediates neurite outgrowth. In cells coexpressing Tiam1 and ephrin-B1, Rac1 is activated by the extracellular stimulation of clustered soluble EphB2 receptors. Similarly, soluble ephrin-A1 activates Rac1 in cells coexpressing Tiam1 and EphA2. Cortical neurons from the E14 mouse embryos and neuroblastoma cells significantly extend neurites when placed on surfaces coated with the extracellular domain of EphB2 or ephrin-A1, which were abolished by the forced expression of the dominant-negative mutant of ephrin-B1 or EphA2. Furthermore, the introduction of a dominant-negative form of Tiam1 also inhibits neurite outgrowth induced by the ephrin-B1 and EphA2 signals. These results indicate that Tiam1 is required for neurite outgrowth induced by both ephrin-B1-mediated reverse signaling and EphA2-mediated forward signaling.

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Section: Discussionmentioning

confidence: 98%

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

Tanaka

Ohashi

Nakamura

et al. 2004

EMBO J

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“…PIP5KI catalyzes the formation of phosphatidylinositol 4,5-bisphosphate, which acts as a negative regulator of neurite elongation by promoting microtubule depolymerization (31). Rac1 plays a crucial role in several aspects of neural development including neuronal migration, axon formation, and neural progenitor proliferation and survival by coordinating both actin and microtubule remodeling (32,33). However, although a direct role for ARF6 in neuronal migration and cortical layering has not yet been reported, we find that the fine-tuning of ARF6 activity by TBC1D24 is important for radial migration.…”

Section: Discussionmentioning

confidence: 99%

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

Falace

Buhler

Fadda

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant-negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development.dendritogenesis | synaptogenesis | epileptic encephalopathies | gene | RNA interferenceT he mammalian cerebral cortex is a multilayered structure derived from cells of the neural tube (1). Cortical projection neurons are generated from proliferating progenitor cells located in the ventricular zone (VZ) adjacent to the lateral ventricle (2). After their final mitotic division, the majority of neurons migrate radially, along radial glia fibers, from the VZ toward the pial surface, where each successive generation passes one another and settles in an inside-out pattern within the cortical plate (CP) (3, 4). When neurons reach their final destination, they stop migrating and order themselves into specific "architectonic" patterns, according to a complex signaling pathway, guiding cells to the correct location in the brain (5). Overall, these steps lead to the formation of a six-layered cortex that plays a key role in cognitive processes. It is therefore not surprising that disruption of early cortical development causes severe neurological conditions usually featuring intellectual disabilities (IDs) and epilepsy, which may be associated with brain malformations (6).Over the past decades, advances in our understanding of the genetics of ID and epilepsy have revolutionized the diagnostic and the clinical approach to these disorders, and an increasing number of pathogenic gene mutations have been identified. TBC1D24 is a novel epilepsy-related gene mutated in different autosomal recessive forms of early-onset epilepsy, which can be accompanied by variable degrees of ID (7-11). The TBC1D24 gene encodes a protein of 553 aa that contains a Tre2/Bub2/Cdc16 (TBC) domain, shared by Rab GTPase-activating proteins (Rab-GAPs) and a TLDc domain of unknown function (8). The TBC1D24 protein is expressed in the brain and interacts with the ADP ribosylation factor (ARF) 6, a small GTP-binding prot...

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“…Tiam1 was identified first in 1994 by in vitro selection for invasiveness in T-lymphoma cells (Habets et al, 1994). Accordingly, Tiam1 has been shown to increase invasion in T-lymphoma cells, as well as to increase cellular migration in fibroblasts, and to promote motility in some neuronal cells (Kawauchi et al, 2003). In contrast, Tiam1 has been demonstrated to increase cellular adhesion in some epithelial cell populations.…”

Section: Discussionmentioning

confidence: 99%

miRNA-218 Inhibits Osteosarcoma Cell Migration and Invasion by Down-regulating of TIAM1, MMP2 and MMP9

Jin

Cai²,

Liu³

et al. 2013

Asian Pacific Journal of Cancer Prevention

103

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Deregulated miRNAs participate in osteosarcoma genesis. In this study, the expression of miRNA-218 in human osteosarcomas, adjacent normal tissues and Saos-2 human osteosarcoma cells was first assessed. Then the precise role of miRNA-218 in osteosarcoma cells was investigated. Upon transfection with a miR-218 expression vector, the proliferation of Saos-2 human osteosarcoma cells determined using the ATPlite assay was significantly suppressed, whilw migration of Saos-2 cells detected by wound healing and invasion determined using transwells were dramatically inhibited. Potential target genes of miR-218 were predicted and T-cell lymphoma invasion and metastasis 1 (TIAM1) and matrix metalloproteinase 2 (MMP2) and 9 (MMP9) were identified. This was confirmed by western blotting, which showed that miR-218 expression inhibited TIAM1, MMP2 and MMP9 protein expression. Collectively, these data suggest that miR-218 acts as a tumor suppressor in osteosarcomas by down-regulating TIAM1, MMP2 and MMP9 expression.

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The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration

Cited by 282 publications

References 51 publications

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2

TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway

miRNA-218 Inhibits Osteosarcoma Cell Migration and Invasion by Down-regulating of TIAM1, MMP2 and MMP9

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