title: The atypical Guanine-nucleotide exchange factor, dock7, negatively regulates schwann cell differentiation and myelination.
abstract: In development of the peripheral nervous system, Schwann cells proliferate, migrate, and ultimately differentiate to form myelin sheath. In all of the myelination stages, Schwann cells continuously undergo morphological changes; however, little is known about their underlying molecular mechanisms. We previously cloned the dock7 gene encoding the atypical Rho family guanine-nucleotide exchange factor (GEF) and reported the positive role of Dock7, the target Rho GTPases Rac/Cdc42, and the downstream c-Jun N-terminal kinase in Schwann cell migration (Yamauchi et al., 2008). We investigated the role of Dock7 in Schwann cell differentiation and myelination. Knockdown of Dock7 by the specific small interfering (si)RNA in primary Schwann cells promotes dibutyryl cAMP-induced morphological differentiation, indicating the negative role of Dock7 in Schwann cell differentiation. It also results in a shorter duration of activation of Rac/Cdc42 and JNK, which is the negative regulator of myelination, and the earlier activation of Rho and Rho-kinase, which is the positive regulator of myelination. To obtain the in vivo evidence, we generated Dock7 short hairpin (sh)RNA transgenic mice. They exhibited a decreased expression of Dock7 in the sciatic nerves and enhanced myelin thickness, consistent with in vitro observation. The effects of the in vivo knockdown on the signals to Rho GTPases are similar to those of the in vitro knockdown. Collectively, the signaling through Dock7 negatively regulates Schwann cell differentiation and the onset of myelination, demonstrating the unexpected role of Dock7 in the interplay between Schwann cell migration and myelination.
authors: Department of Pharmacology and Laboratory Animal Resource Facility, National Research Institute for Child Health and Development, Setagaya, Tokyo 157-8535, Japan. jyamauchi@nch.go.jp
authors: Junji
authors: J
authors: Yamauchi
authors: Yuki
authors: Y
authors: Miyamoto
authors: Hajime
authors: H
authors: Hamasaki
authors: Atsushi
authors: A
authors: Sanbe
authors: Shinji
authors: S
authors: Kusakawa
authors: Akane
authors: A
authors: Nakamura
authors: Hideki
authors: H
authors: Tsumura
authors: Masahiro
authors: M
authors: Maeda
authors: Noriko
authors: N
authors: Nemoto
authors: Katsumasa
authors: K
authors: Kawahara
authors: Tomohiro
authors: T
authors: Torii
authors: Akito
authors: A
authors: Tanoue
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D020690:GTPase-Activating Proteins; D005727:Ganglia, Spinal / Q000166:cytology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D047468:Immunoprecipitation / Q000379:methods; D007211:Indoles; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D009186:Myelin Sheath / Q000378:metabolism* / Q000648:ultrastructure; D020890:Neuregulin-1 / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012583:Schwann Cells / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D012584:Sciatic Nerve / Q000166:cytology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: C539620:Dock7 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D007211:Indoles; D020890:Neuregulin-1; D034741:RNA, Small Interfering; C007293:DAPI; D003994:Bucladesine; D017346:Protein Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein; D020741:rho GTP-Binding Proteins