Su D, Ellis S, Napier A, Lee K, Manley N R
Institute of Molecular Medicine and Genetics, Medical College of Georgia, Augusta, Georgia 30912, USA.
Dev Biol. 2001 Aug 15;236(2):316-29. doi: 10.1006/dbio.2001.0342.
The thymus and parathyroid glands in mice develop from a thymus/parathyroid primordium that forms from the endoderm of the third pharyngeal pouch. We investigated the molecular mechanisms that promote this unique process in which two distinct organs form from a single primordium, using mice mutant for Hoxa3 and Pax1. Thymic ectopia in Hoxa3(+/-)Pax1(-/-) compound mutants is due to delayed separation of the thymus/parathyroid primordium from the pharynx. The primordium is hypoplastic at its formation, and has increased levels of apoptosis. The developing third pouch in Hoxa3(+/-)Pax1(-/-) compound mutants initiates normal expression of the parathyroid-specific Gcm2 and thymus-specific Foxn1 genes. However, Gcm2 expression is reduced at E11.5 in Pax1(-/-) single mutants, and further reduced or absent in Hoxa3(+/-)Pax1(-/-) compound mutants. Subsequent to organ-specific differentiation from the shared primordium, both the parathyroids and thymus developed defects. Parathyroids in compound mutants were smaller at their formation, and absent at later stages. Parathyroids were also reduced in Pax1(-/-) mutants, revealing a new function for Pax1 in parathyroid organogenesis. Thymic hypoplasia at later fetal stages in compound mutants was associated with increased death and decreased proliferation of thymic epithelial cells. Our results suggest that a Hoxa3-Pax1 genetic pathway is required for both epithelial cell growth and differentiation throughout thymus and parathyroid organogenesis.
小鼠的胸腺和甲状旁腺由一个胸腺/甲状旁腺原基发育而来，该原基由第三咽囊的内胚层形成。我们利用Hoxa3和Pax1基因敲除小鼠，研究了促进这一独特过程（即从单个原基形成两个不同器官）的分子机制。Hoxa3(+/-)Pax1(-/-)复合突变体中的胸腺异位是由于胸腺/甲状旁腺原基与咽的分离延迟所致。原基在形成时发育不全，且凋亡水平升高。Hoxa3(+/-)Pax1(-/-)复合突变体中发育中的第三咽囊启动了甲状旁腺特异性Gcm2基因和胸腺特异性Foxn1基因的正常表达。然而，在Pax1(-/-)单突变体中，E11.5时Gcm2表达降低，在Hoxa3(+/-)Pax1(-/-)复合突变体中进一步降低或缺失。在从共同原基进行器官特异性分化之后，甲状旁腺和胸腺都出现了缺陷。复合突变体中的甲状旁腺在形成时较小，后期则缺失。Pax1(-/-)突变体中的甲状旁腺也减少了，这揭示了Pax1在甲状旁腺器官发生中的新功能。复合突变体在胎儿后期的胸腺发育不全与胸腺上皮细胞死亡增加和增殖减少有关。我们的结果表明，Hoxa3 - Pax1基因通路在整个胸腺和甲状旁腺器官发生过程中对于上皮细胞的生长和分化都是必需的。
