| Budget Amount *help |
¥14,800,000 (Direct Cost: ¥14,800,000)
Fiscal Year 2006: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2005: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2004: ¥7,400,000 (Direct Cost: ¥7,400,000)
|
|---|
| Research Abstract |
Axon guidance represents a key stage in the formation of neuronal network. Axons are guided by a variety of guidance factors, such as semaphorins, ephrins, and netrins. Plexins function as receptors for repylsive axonal guidance molecules, semaphorins. We have revealed that the semaphorin 4D, Sema4D, receptor Plexin-B1 directly stimulates the intrinsic GAPase activity of R-Ras, which has been shown to promote neurite outgrowth by activating integrins, in response to sema4D. The down regulation of R-Ras activity by the Plexin-B1 is essential for the Sema4D-induced frowth cone collapse in hippocampal neurons. In addition, the downregulation of R-Ras activity is also required for the Sema3A-induced growth cone collapse. Thus, Plexins mediate semaphorin-induced repulsive signaling by acting as a GAP for R-Ras. We have further characterized the downstream signaling of Plexin-B1-mediated R-Ras GAP activity. Sema4D suppressed R-Ras activity in hippocampal neurons and dephosphorylated Akt and
… More
GSK3 and phosphorylated CRMP-2, a microtubule polumerization stimulator, through its inhibition of R-Ras activity. We also found that Sema3A dephosphorylates Akt and GSK3. Therefore, Plexins inactivate PI-3K and Akt, and activate GSK3 through R-Ras GAP activity, inducing growth cone collapse.
The Rho family of small GTPases has been implicated in the reorganization of actin cytoskeleton and subsequent morphological changes in various cells. Rnd2 is a member of the Rnd subfamily, comprising Rnd1, Rnd2, and Rnd3. In contrast to Rnd1 and Rnd3, displaying an antagonistic action for RhoA signaling, signaling pathways of Rnd2 are not well known. We have performed a yeast two-hybrid screen using Rnd2 as bait and identified a novel Rnd2 effector protein, predominantly expressed in neurons, including cortical and hippocampal neurons. We named it Pragmin. Pragmin stimulates RhoA activity in response to Rnd2, inducing cell contraction and neurite retraction. Therefore, Rnd2 regulates neurite outgrowth by functioning as the RhoA activator through Pragmin, in contrast to Rnd1 and Rnd3 inhibiting RhoA signaling. Less
|
