Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse
Genetic deletion of sonic hedgehog causes hemiagenesis and ectopic development of the thyroid in mouse
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DOI：
10.1016/s0002-9440(10)63745-5
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发表时间：
2004-05-01
影响因子：
6
通讯作者：
Nilsson, M
中科院分区：
文献类型：
--
作者：
Fagman, H;Grände, M;Nilsson, M
85%的先天性甲状腺功能减退症患者出现甲状腺发育不全，这是一种形态上异质性的疾病，发病机制基本上未知。在这里，我们确定音刺猬（嘘）作为一种新的调节甲状腺发育。在Shh基因敲除小鼠中，甲状腺原基在咽内胚层中被正确地指定，但是出芽和脱位稍微延迟。在发育后期，甲状腺不能形成双叶腺。相反，在单侧发现单个甲状腺肿块，且大部分位于中线左侧。甲状腺特异性转录因子（TTF-1和TTF-2）和甲状腺球蛋白的表达表明终末分化。值得注意的是，TTF-1和TTF-2阳性细胞在Shh-1胚胎的假定气管中异常发育。异位组织从腹外侧出芽进入邻近的间充质，较少进入气管腔，形成聚集甲状腺球蛋白的滤泡样结构。Shh mRNA在任何发育阶段的甲状腺前体细胞中均不表达。结果表明，Shh信号间接地控制甲状腺在器官发生后期的对称双叶。Shh似乎也抑制非甲状腺胚胎组织中的甲状腺分化。本研究为甲状腺偏侧发育不全和甲状舌管外异位甲状腺组织的发生提供了分子机制的线索。
Thyroid dysgenesis encountered in 85% of patients with congenital hypothyroidism is a morphologically heterogeneous condition with primarily unknown pathogenesis. Here we identify sonic hedgehog (Shh) as a novel regulator of thyroid development. In Shh knockout mice the thyroid primordium is correctly specified in the pharyngeal endoderm, but budding and dislocation are slightly delayed. in late development the thyroid fails to form a bilobed gland. instead a single thyroid mass is found unilaterally and mostly to the left of the midline. Thyroid-specific transcription factors (TTF-1 and TTF-2) and thyroglobulin are expressed indicating terminal differentiation. Strikingly, TTF-1- and TTF-2-positive cells aberrantly develop in the presumptive trachea of Shh-1- embryos. The ectopic tissue buds ventrolaterally into the adjacent mesenchyme, and less extensively into the tracheal lumen, forming follicle-like structures that accumulate thyroglobulin. Shh mRNA is not expressed in the thyroid precursor cells at any developmental stage. The results indicate that Shh signaling indirectly governs the symmetric bilobation of the thyroid during late organogenesis. Shh also seems to repress inappropriate thyroid differentiation in non-thyroid embryonic tissues. This study provides clues to the molecular mechanisms that might be dysregulated in thyroid hemiagenesis and development of ectopic thyroid tissue outside the thyroglossal duct.