RT Journal Article
SR Electronic
T1 GDNF and Endothelin 3 Regulate Migration of Enteric Neural Crest-Derived Cells via Protein Kinase A and Rac1
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4901
OP 4912
DO 10.1523/JNEUROSCI.4828-12.2013
VO 33
IS 11
A1 Goto, Akihiro
A1 Sumiyama, Kenta
A1 Kamioka, Yuji
A1 Nakasyo, Eiji
A1 Ito, Keisuke
A1 Iwasaki, Mitsuhiro
A1 Enomoto, Hideki
A1 Matsuda, Michiyuki
YR 2013
UL http://www.jneurosci.org/content/33/11/4901.abstract
AB Enteric neural crest-derived cells (ENCCs) migrate from the anterior foregut in a rostrocaudal direction to colonize the entire gastrointestinal tract and to form the enteric nervous system. Genetic approaches have identified many signaling molecules regulating the migration of ENCCs; however, it remains elusive how the activities of the signaling molecules are regulated spatiotemporally during migration. In this study, transgenic mice expressing biosensors based on Förster resonance energy transfer were generated to video the activity changes of the signaling molecules in migrating ENCCs. In an organ culture of embryonic day 11.25 (E11.25) to E13 guts, ENCCs at the rostral wavefront migrated as a cellular chain faster than the following ENCCs that formed a network. The faster-migrating cells at the wavefront exhibited lower protein kinase A (PKA) activity than did the slower-migrating trailing cells. The activities of Rac1 and Cdc42 exhibited an inverse correlation with the PKA activity, and PKA activation decreased the Rac1 activity and migration velocity. PKA activity in ENCCs was correlated positively with the distribution of GDNF and inversely with the distribution of endothelin 3 (ET-3). Accordingly, PKA was activated by GDNF and inhibited by ET-3 in cultured ENCCs. Finally, although the JNK and ERK pathways were previously reported to control the migration of ENCCs, we did not find any correlation of JNK or ERK activity with the migration velocities. These results suggest that external cues regulate the migration of ENCCs by controlling PKA activity, but not ERK or JNK activity, and argue for the importance of live imaging of signaling molecule activities in developing organs.