title: The Neuregulin-Rac-MKK7 pathway regulates antagonistic c-jun/Krox20 expression in Schwann cell dedifferentiation.
abstract: Schwann cells respond to nerve injury by dedifferentiating into immature states and producing neurotrophic factors, two actions that facilitate successful regeneration of axons. Previous reports have implicated the Raf-ERK cascade and the expression of c-jun in these Schwann cell responses. Here we used cultured primary Schwann cells to demonstrate that active Rac1 GTPase (Rac) functions as a negative regulator of Schwann cell differentiation by upregulating c-jun and downregulating Krox20 through the MKK7-JNK pathway, but not through the Raf-ERK pathway. The activation of MKK7 and induction of c-jun in sciatic nerves after axotomy was blocked by Rac inhibition. Microarray experiments revealed that the expression of regeneration-associated genes, such as glial cell line-derived neurotrophic factor and p75 neurotrophin receptor, after nerve injury was dependent on Rac but not on ERK. Finally, the inhibition of ErbB2 signaling prevented MKK7 activation, c-jun induction, and Rac-dependent gene expression in sciatic nerve explant cultures. Taken together, our results indicate that the neuregulin-Rac-MKK7-JNK/c-jun pathway regulates Schwann cell dedifferentiation following nerve injury.
authors.affiliation: Department of Physiology and Mitochondria Hub Regulation Center (MHRC), College of Medicine, Dong-A University, Busan, South Korea.
authors.forename: Yoon Kyung
authors.initials: YK
authors.lastname: Shin
authors.forename: So Young
authors.initials: SY
authors.lastname: Jang
authors.forename: Joo Youn
authors.initials: JY
authors.lastname: Park
authors.forename: So Young
authors.initials: SY
authors.lastname: Park
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Lee
authors.forename: Duk Joon
authors.initials: DJ
authors.lastname: Suh
authors.forename: Hwan Tae
authors.initials: HT
authors.lastname: Park
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D000818:Animals; D054337:Cell Dedifferentiation / Q000187:drug effects / Q000502:physiology*; D051767:Early Growth Response Protein 2 / Q000378:metabolism*; D048688:MAP Kinase Kinase 7 / Q000378:metabolism*; D051379:Mice; D020890:Neuregulin-1 / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D012583:Schwann Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D012584:Sciatic Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D000634:Aminoquinolines; D051767:Early Growth Response Protein 2; C487513:NSC 23766; D020890:Neuregulin-1; D016755:Proto-Oncogene Proteins c-jun; D011743:Pyrimidines; D051057:Proto-Oncogene Proteins c-akt; D048688:MAP Kinase Kinase 7; C482570:Map2k7 protein, mouse