Cameron Don A, Pennimpede Tracie, Petkovich Martin
Department of Biochemistry, Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
Dev Dyn. 2009 May;238(5):1140-9. doi: 10.1002/dvdy.21926.
Precise regulation of the morphogen sonic hedgehog (Shh) and modulation of the Shh signaling pathway is required for proper specification of cell fate within the developing limbs and neural tube, and resultant tissue morphogenesis. Tulp3 (tubby-like protein 3) is a protein of unknown function which has been implicated in nervous system development through gene knockout studies. We demonstrate here that mice lacking the Tulp3 gene develop abnormalities of both the neural tube and limbs consistent with improper regulation of Shh signaling. Tulp3(-/-) embryos show expansion of Shh target gene expression and display a ventralization of neural progenitor cells in the caudal neural tube. We further show that Tulp3(-/-)/Shh(-/-) compound mutant embryos resemble Tulp3 mutants, and express Shh target genes in the neural tube and limbs which are not expressed in Shh(-/-) embryos. This work uncovers a novel role for Tulp3 as a negative regulatory factor in the Hh pathway.
形态发生素音猬因子（Shh）的精确调控以及Shh信号通路的调节，对于发育中的肢体和神经管内细胞命运的正确特化以及由此产生的组织形态发生是必需的。Tulp3（类tubby蛋白3）是一种功能未知的蛋白质，通过基因敲除研究表明其与神经系统发育有关。我们在此证明，缺乏Tulp3基因的小鼠会出现神经管和肢体异常，这与Shh信号调节不当一致。Tulp3(-/-)胚胎显示Shh靶基因表达增加，并在尾侧神经管中表现出神经祖细胞的腹侧化。我们进一步表明，Tulp3(-/-)/Shh(-/-)复合突变胚胎与Tulp3突变体相似，并在神经管和肢体中表达Shh靶基因，而这些基因在Shh(-/-)胚胎中不表达。这项工作揭示了Tulp3作为Hh通路中的负调控因子的新作用。
