Regulation of hippocampal neuronal differentiation by the basic helix-loop-helix transcription factors HES-1 and MASH-1.
HES-1 is a vertebrate homologue of the Drosophila basic helix-loop-helix (bHLH) protein Hairy, a transcriptional repressor that negatively regulates neuronal differentiation. HES-1 expression in neuronal precursors precedes and represses the expression of the neuronal commitment gene MASH-1, a bHLH activator homologous to the proneural Achaete-Scute genes in Drosophila. Down-regulation of HES-1 expression in developing neuroblasts may be necessary for the induction of a regulatory cascade of bHLH activator proteins that controls the commitment and progression of neuronal differentiation. Here we show that the differentiation of embryonic day-17 rat hippocampal neurons in culture was coincident with a decline in HES-1 expression and DNA binding. Therefore, we examined the effect of forced expression of HES-1 and MASH-1 upon nerve growth factor (NGF) -induced differentiation in TrkA transfected hippocampal neurons. Expression of HES-1 inhibited both the intrinsic and NGF-induced neurite outgrowth, whereas MASH-1 expression increased neurite outgrowth. Strikingly, the increased hippocampal differentiation observed with MASH-1 expression is completely blocked by coexpression of HES-1. Furthermore, both wild-type HES-1 and a non-DNA binding mutant of HES-1 repressed MASH-1-dependent transcription activation. These results suggest that down-regulation of HES-1 is necessary for autonomous, growth factor-induced and MASH-1-activated hippocampal differentiation.
Castella
P
P
Cell Biology and Genetics Graduate Program, Cornell University Graduate School of Medical Sciences, New York, New York 10021, USA.
Wagner
J A
JA
Caudy
M
M
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins; D002454:Cell Differentiation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018257:Helix-Loop-Helix Motifs; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D009414:Nerve Growth Factors / Q000494:pharmacology; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D016716:PC12 Cells; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000502:physiology; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D009414:Nerve Growth Factors; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA; D017475:Receptors, Nerve Growth Factor; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C499318:Ascl1 protein, rat; C489735:Hes1 protein, rat