Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix-loop-helix transcription factors Mash1 and Math1.
Neurogenesis is promoted by basic helix-loop-helix (bHLH) transcription factors Mash1, Math1, or NeuroD but suppressed by another set, Hes1 and Hes5. It remains unknown what kinds of extracellular signals are involved in their regulation; therefore, the effects of neurotrophins on the expression of bHLH factors and neuronal differentiation were investigated by the use of cultured mouse neural stem cells. Each neurotrophin increased Mash1 and Math1 mRNAs of the stem cells growing in the presence of fibroblast growth factor-2 (FGF-2), but did not alter Hes1, Hes5, or NeuroD mRNA levels. Simultaneously, most of the cells expressed nestin but not microtubule-associated protein 2 (MAP2), and remained undifferentiated. FGF-2 removal from the medium reduced the levels of Hes1 and Hes5 mRNAs and increased those of Mash1, Math1, and NeuroD mRNAs, resulting in substantial neuronal differentiation. When the cells were pretreated with brain-derived neurotrophic factor, a neurotrophin, FGF-2 removal enhanced earlier NeuroD expression and generated many more MAP2-positive cells. The high level of Mash1 and Math1 that had been elevated at FGF-2 withdrawal accelerated NeuroD expression in cooperation with the reduced Hes1 and Hes5 expression. Our present results suggest that neurotrophins stimulate neuronal differentiation by altering the balance of expression of various bHLH transcription factors.
Ito
Hisanori
H
Laboratory of Molecular Biology, Gifu Pharmaceutical University, Gifu, Japan.
Nakajima
Aki
A
Nomoto
Hiroshi
H
Furukawa
Shoei
S
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018257:Helix-Loop-Helix Motifs; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D009474:Neurons / Q000166:cytology / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D013687:Telencephalon / Q000166:cytology / Q000196:embryology; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D004268:DNA-Binding Proteins; D016222:Fibroblast Growth Factor 2; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C500943:Atoh1 protein, mouse; C489734:Hes1 protein, mouse; C489685:Hes5 protein, mouse; C077478:HES5 protein, human; C093564:Neurogenic differentiation factor 1