Cdo promotes neuronal differentiation via activation of the p38 mitogen-activated protein kinase pathway.
Neural basic helix-loop-helix transcription factors (bHLHs) control many aspects of neurogenesis, such as proliferation, fate determination, and differentiation. We have previously shown that the promyogenic cell surface receptor Cdo modulates the Cdc42 and p38 mitogen-activated protein kinase (MAPK) pathways via a direct association with two scaffold-type proteins, JLP and Bnip-2, to regulate activities of myogenic bHLH factors and myogenic differentiation. We report here that Cdo uses similar regulatory mechanisms to promote neuronal differentiation. Expression of JLP, a scaffold protein for p38MAPK, and Bnip-2, a regulator of Cdc42, is increased during differentiation of C17.2 neural precursor cells and P19 embryonal carcinoma cells. These molecules regulate Cdc42 and p38MAPK activities, which increase in a Cdo-dependent manner during neuronal differentiation of C17.2 cells and retinoic acid-treated P19 cells. Furthermore, enhancement or reduction of Cdc42 and p38MAPK activities enhances or reduces, respectively, neuronal differentiation of these cell lines. Cdc42 and p38MAPK activities also promote heterodimerization of neurogenin1 and E47, suggesting that one way they promote neurogenesis is via regulation of neural bHLH factor activities. These results imply that a conserved intracellular signaling mechanism initiated by Cdo regulates the activities of tissue-specific bHLH factors and therefore functions as a key regulator of differentiation of several different cell lineages.
Oh
Ji-Eun
JE
Samsung Biomedical Research Institute, Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, South Korea.
Bae
Gyu-Un
GU
Yang
Youn-Joo
YJ
Yi
Min-Jeong
MJ
Lee
Hye-Jin
HJ
Kim
Bok-Geon
BG
Krauss
Robert S
RS
Kang
Jong-Sun
JS
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D019070:Cell Lineage; D004789:Enzyme Activation; D051379:Mice; D018345:Mice, Knockout; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D051792:Basic Helix-Loop-Helix Proteins; D015815:Cell Adhesion Molecules; D020764:cdc42 GTP-Binding Protein; D048051:p38 Mitogen-Activated Protein Kinases; C510744:Cdon protein, mouse