title: Basic helix-loop-helix transcription factors regulate the neuroendocrine differentiation of fetal mouse pulmonary epithelium.
abstract: To clarify the mechanisms that regulate neuroendocrine differentiation of fetal lung epithelia, we have studied the expression of the mammalian homologs of achaete-scute complex (Mash1) (Ascl1 - Mouse Genome Informatics); hairy and enhancer of split1 (Hes1); and the expression of Notch/Notch-ligand system in the fetal and adult mouse lungs, and in the lungs of Mash1- or Hes1-deficient mice. Immunohistochemical studies revealed that Mash1-positive cells seemed to belong to pulmonary neuroendocrine cells (PNEC) and their precursors. In mice deficient for Mash1, no PNEC were detected. Hes1-positive cells belong to non-neuroendocrine cells. In the mice deficient in Hes1, in which Mash1 mRNA was upregulated, PNEC appeared precociously, and the number of PNEC was markedly increased. NeuroD (Neurod1 - Mouse Genome Informatics) expression in the lung was detected in the adult, and was enhanced in the fetal lungs of Hes1-null mice. Expression of Notch1, Notch2, Notch3 and Notch4 mRNAs in the mouse lung increased with age, and Notch1 mRNA was expressed in a Hes1-dependent manner. Notch1, Notch2 and Notch3 were immunohistochemically detected in non-neuroendocrine cells. Moreover, analyses of the lungs from the gene-targeted mice suggested that expression of Delta-like 1 (Dll1 - Mouse Genome Informatics) mRNA depends on Mash1. Thus, the neuroendocrine differentiation depends on basic helix-loop-helix factors, and Notch/Notch-ligand pathways may be involved in determining the cell differentiation fate in fetal airway epithelium.
authors.affiliation: Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan. takaito@med.yokohama-cu.ac.jp.
authors.forename: T
authors.initials: T
authors.lastname: Ito
authors.forename: N
authors.initials: N
authors.lastname: Udaka
authors.forename: T
authors.initials: T
authors.lastname: Yazawa
authors.forename: K
authors.initials: K
authors.lastname: Okudela
authors.forename: H
authors.initials: H
authors.lastname: Hayashi
authors.forename: T
authors.initials: T
authors.lastname: Sudo
authors.forename: F
authors.initials: F
authors.lastname: Guillemot
authors.forename: R
authors.initials: R
authors.lastname: Kageyama
authors.forename: H
authors.initials: H
authors.lastname: Kitamura
mesh_terms: D000375:Aging / Q000235:genetics / Q000502:physiology; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins; D001824:Body Constitution; D002452:Cell Count; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D029721:Drosophila Proteins; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018257:Helix-Loop-Helix Motifs; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D008024:Ligands; D008168:Lung / Q000166:cytology* / Q000196:embryology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D018398:Homeodomain Proteins; D008024:Ligands; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C499317:Ascl1 protein, mouse; C489734:Hes1 protein, mouse; C089199:ac protein, Drosophila; C089197:sc protein, Drosophila; C093564:Neurogenic differentiation factor 1