Ito T, Udaka N, Yazawa T, Okudela K, Hayashi H, Sudo T, Guillemot F, Kageyama R, Kitamura H
Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan.
Development. 2000 Sep;127(18):3913-21. doi: 10.1242/dev.127.18.3913.
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.
为阐明调节胎儿肺上皮细胞神经内分泌分化的机制，我们研究了无翅型基因（achaete-scute complex）哺乳动物同源物（Mash1）（Ascl1 - 小鼠基因组信息学）、毛状和分裂增强子1（Hes1）的表达，以及Notch/Notch配体系统在胎儿和成年小鼠肺组织以及Mash1或Hes1基因敲除小鼠肺组织中的表达。免疫组织化学研究显示，Mash1阳性细胞似乎属于肺神经内分泌细胞（PNEC）及其前体。在Mash1基因敲除小鼠中，未检测到PNEC。Hes1阳性细胞属于非神经内分泌细胞。在Hes1基因敲除小鼠中，Mash1 mRNA上调，PNEC早熟出现，且PNEC数量显著增加。在成年小鼠肺组织中检测到NeuroD（Neurod1 - 小鼠基因组信息学）表达，在Hes1基因敲除小鼠的胎儿肺组织中表达增强。小鼠肺组织中Notch1、Notch2、Notch3和Notch4 mRNA的表达随年龄增加，且Notch1 mRNA以Hes1依赖的方式表达。Notch1、Notch2和Notch3在非神经内分泌细胞中通过免疫组织化学检测到。此外，对基因靶向小鼠肺组织的分析表明，Delta样1（Dll1 - 小鼠基因组信息学）mRNA的表达依赖于Mash1。因此，神经内分泌分化依赖于碱性螺旋-环-螺旋因子，Notch/Notch配体途径可能参与决定胎儿气道上皮细胞的分化命运。
