Department of Cell and Developmental Biology, Weill Medical College of Cornell University, New York, New York, United States of America.
PLoS One. 2010 Nov 30;5(11):e14134. doi: 10.1371/journal.pone.0014134.
The pair-rule gene, hairy, encodes a basic helix-loop-helix transcription factor and is required for patterning of the early Drosophila embryo and for morphogenesis of the embryonic salivary gland. Although hairy was shown to be expressed in the tracheal primordia and in surrounding mesoderm, whether hairy plays a role in tracheal development is not known.
Here, we report that hairy is required for refining the terminal cell fate in the embryonic trachea and that hairy's tracheal function is distinct from its earlier role in embryonic patterning. In hairy mutant embryos where the repressive activity of hairy is lost due to lack of its co-repressor binding site, extra terminal cells are specified in the dorsal branches. We show that hairy functions in the muscle to refine the terminal cell fate to a single cell at the tip of the dorsal branch by limiting the expression domain of branchless (bnl), encoding the FGF ligand, in surrounding muscle cells. Abnormal activation of the Bnl signaling pathway in hairy mutant tracheal cells is exemplified by increased number of dorsal branch cells expressing Bnl receptor, Breathless (Btl) and Pointed, a downstream target of the Bnl/Btl signaling pathway. We also show that hairy genetically interacts with bnl in TC fate restriction and that overexpression of bnl in a subset of the muscle surrounding tracheal cells phenocopied the hairy mutant phenotype.
CONCLUSIONS/SIGNIFICANCE: Our studies demonstrate a novel role for Hairy in restriction of the terminal cell fate by limiting the domain of bnl expression in surrounding muscle cells such that only a single dorsal branch cell becomes specified as a terminal cell. These studies provide the first evidence for Hairy in regulation of the FGF signaling pathway during branching morphogenesis.
成对规则基因 hairy 编码一个基本的螺旋-环-螺旋转录因子，对于果蝇早期胚胎的模式形成和胚胎唾液腺的形态发生是必需的。尽管 hairy 被证明在气管原基和周围的中胚层中表达，但它是否在气管发育中起作用尚不清楚。
在这里，我们报告 hairy 对于细化胚胎气管中的终末细胞命运是必需的，并且 hairy 的气管功能与其在早期胚胎模式形成中的作用不同。在 hairy 突变体胚胎中，由于缺乏其共抑制物结合位点，其抑制活性丧失，导致背支中额外的终末细胞被指定。我们表明，通过限制分支less(bnl)的表达域，在周围的肌肉细胞中，hairy 在肌肉中发挥作用，以将终末细胞命运细化为背支尖端的单个细胞。编码 FGF 配体的 bnl，表明 hairy 突变体气管细胞中 Bnl 信号通路的异常激活，在背支细胞中表达 Bnl 受体 Breathless（Btl）和 Pointed 的细胞数量增加，这是 Bnl/Btl 信号通路的下游靶标。我们还表明，在 TC 命运限制中，hairy 与 bnl 存在遗传相互作用，并且 bnl 在围绕气管细胞的肌肉的一部分中的过表达模拟了 hairy 突变体表型。
结论/意义：我们的研究表明，Hairy 通过限制周围肌肉细胞中 bnl 表达的域来限制终末细胞命运，从而仅指定单个背支细胞成为终末细胞，从而在限制终末细胞命运中发挥了新的作用。这些研究提供了 hairy 在分支形态发生过程中调节 FGF 信号通路的第一个证据。
