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

bHLH转录因子Mash1在神经嵴细胞向自主神经元分化的过程中起关键作用。Mash1缺失突变小鼠缺乏交感神经节、嗅觉受体神经元、肺神经内分泌细胞和颈动脉体血管球细胞。甲状腺C细胞合成并分泌血清降钙激素降钙素。由第四咽袋衍生的鳃末小体进入甲状腺成为C细胞。为了阐明C细胞从其终鳃祖细胞分化的分子机制，本研究检测了Mash1零突变胚胎和新生儿的终鳃体和C细胞的发育，并与野生型进行了比较。新生小鼠甲状腺C细胞对CGRP、PGP9有免疫反应。5和NeuroD，并短暂地表现出神经元标记物Tun。以及胎儿发育过程中的生长抑素。Mash1在胚胎期(E) 12.5时在鳃裂小体中表达，在胚胎期(E) 13.5时在甲状腺叶融合器官中也表达。靶向破坏Mash1导致小鼠甲状腺中C细胞缺失。虽然Mash1零突变体的形成和迁移不受影响，但在E12.5-E13.5时，多鳃体和填充甲状腺叶的器官都表现出凋亡细胞数量的显著增加。因此，在突变小鼠中，终鳃体不能完成其分化程序，最终死亡。这些结果表明，mash1依赖性信号通路在c细胞发育中起重要作用。在器官发生过程中，神经嵴细胞未在多鳃小体中定植。另一方面，所有鳃末细胞以及第4咽袋上皮对上皮标志物e -钙粘蛋白具有强烈的免疫反应。此外，在新生小鼠甲状腺中，共聚焦显微镜证实了降钙素和e -钙粘蛋白的共定位。因此，小鼠甲状腺C细胞来源于第四咽袋的内胚层上皮细胞，而不是神经嵴细胞。Mash1可能诱导来自内胚层的C细胞的神经元特性。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