Abstract
Cell migration is a complex biological process playing a key role in physiological and pathological conditions. During central nervous system development, positioning and function of cortical neurons is tightly regulated by cell migration. Recently, signaling events involving the urokinase-type plasminogen activator receptor, which is a key regulator for the activation of hepatocyte growth factor (HGF), have been implicated in modulating cortical neuron migration. However, the intracellular pathways controlling neuronal migration triggered by the HGF receptor Met have not been elucidated. By combining pharmacological and genetic approaches, we show here that the Ras/ERK pathway and phosphatidylinositol 3-kinase (PI3K) are both required for cortical neuron migration. By dissecting the downstream signals necessary for this event, we found that Rac1/p38 and Akt are required, whereas the c-Jun N-terminal kinase (JNK) and mTOR/p70(s6k) pathways are dispensable. This study demonstrates that concomitant activation of the Ras/ERK, PI3K/Akt, and Rac1/p38 pathways is required to achieve full capacity of cortical neurons to migrate upon HGF stimulation.
Highlights
Recent studies have suggested that hepatocyte growth factor (HGF)5 signaling can elicit trans-telencephalic migration of interneu
ERK Signaling Is Required for Cortical Neuron Migration Induced by HGF— several reports have shown that the Ras/ERK pathway contributes to Met-triggered cell migration in epithelial cells [25, 27, 29, 43], this signal is dispensable for HGF-induced migration of striatal
HGF-induced migration was assayed in met2P/2P and met2S/2S neurons. met2P/2P cortical neurons migrate in response to HGF, to a lesser extent compared with wild-type cells (Fig. 1C; p Ͻ 0.001)
Summary
Recent studies have suggested that hepatocyte growth factor (HGF) signaling can elicit trans-telencephalic migration of interneu-. In addition to the motogenic activity, several reports have enlightened the pleiotropic functions triggered by the HGF/Met couple in several types of neurons. Activation of PI3K signaling by Met triggers motogenic responses in fibroblasts and epithelial and muscle cells (29 –32). Genetic analysis of met specificity-switch mutant mice has been instrumental for studying signaling requirement for myoblast migration in vivo. In these mice, the multifunctional docking sites of Met have been replaced by specific binding motifs for PI3K (Met2P) or Src (Met2S) [38]. The early embryonic lethality of met mutants has prevented to further study the motogenic activity of other cell types like neurons in vivo. MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; GFP, green fluorescent protein; dn, dominant negative; ca, constitutively active; PBS, phosphate-buffered saline
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
