Molecular mechanisms of thyroid C-cell differentiation using gene targeting mice.

BHLH转录因子Mash1在自主神经细胞向神经脊细胞分化过程中起关键作用。Mash1基因缺失突变小鼠缺乏交感神经节、嗅觉感受器神经元、肺神经内分泌细胞和颈动脉体球细胞。甲状腺C细胞合成和分泌血清降钙激素降钙素。来自第四咽囊的多鳃小体进入甲状腺，成为C细胞。为阐明Mash1基因缺失突变胚胎和新生儿多鳃C细胞分化的分子机制，本研究以野生型为对照，研究了Mash1缺失突变胚胎和新生儿多鳃小体和C细胞的发育。新生小鼠甲状腺C细胞对CGRP、PGP9呈免疫反应。5，和Neurod，并一过性地显示神经元标记Tun。和生长抑素在胎儿发育中的作用。Mash1在胚胎第12.5d在多鳃小体和与…融合的器官中表达在E 13.5处多于甲状腺。靶向干扰Mash1导致小鼠甲状腺中没有C细胞。Mash1缺失突变体对多鳃小体的形成和迁移没有影响，但在E12.5-E13.5，多鳃小体和位于甲状腺小叶的器官的凋亡细胞数均显著增加。因此，在突变小鼠中，多鳃小体未能完成其分化程序，最终死亡。这些结果表明，Mash1依赖的信号通路在C细胞的发育中起着重要作用。在器官发生过程中，多鳃小体不被神经脊细胞定植。另一方面，所有的多鳃细胞以及第四咽囊上皮对上皮标志物E-钙粘素呈强烈的免疫反应。此外，共聚焦显微镜证实了降钙素和E-钙粘素在新生小鼠甲状腺中的共存。因此，小鼠甲状腺C细胞来源于第四咽囊内胚层上皮细胞，而不是神经脊细胞。Mash1可诱导内胚层来源的C细胞分化为神经元。较少

The bHLH transcription factor Mash1 plays a key role in the differentiation of autonomic neurons from neural crest cells. Mash1 null mutant mice lack sympathetic ganglion, olfactory receptor neurons, lung neuroendocrine cells and carotid body glomus cells. Thyroid C cells synthesize and secrete serum calcium-lowering hormone, calcitonin. The ultimobranchial body derived from the fourth pharyngeal pouch enters the thyroid gland to become C cells. To clarify the molecular mechanisms involved in the differentiation of C cells from their ultimobranchial progenitors, the present study examined the development of ultimobranchial body and C cells in Mash1 null mutant embryos and neonates, in comparison with wild types. Thyroid C cells of newborn mice are immunoreactive for CGRP, PGP9. 5, and NeuroD, and transiently exhibit the neuronal markers Tun. and somatostatin during fetal development. Mash1 is expressed at embryonic day (E) 12.5 in the ultimobranchial body and also in the organ fused wi … More th the thyroid lobe at E 13.5. Targeted disruption of Mash1 resulted in the absence of C cells in the mouse thyroid glands. While the formation and migration of the ultimobranchial body were not affected in the Mash1 null mutants, at E12.5-E13.5 both the ultimobranchial body and the organ populating the thyroid lobe exhibited a marked increase in apoptotic cell numbers. Thus, in the mutant mice, the ultimobranchial body fails to complete its differentiation program and finally dies. These results indicate that the Mash1-dependent signaling pathway plays an important role in C-cell development. During the organogenesis, the ultimobranchial bodies were not colonized by the neural crest cells. On the other hand, all ultimobranchial cells, as well as the epithelium of the fourth pharyngeal pouch were intensely immunoreactive for E-cadherin, an epithelial marker. Furthermore, in newborn mouse thyroid glands the colocalization of calcitonin and E-cadherin was confirmed by confocal microscopy. Thus, the mouse thyroid C cells are derived from the endodermal epithelial cells of the fourth pharyngeal pouch and are not from the neural crest cells. Mash1 may induce the neuronal traits in C cells derived from the endoderm. Less