Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors
Submandibular Parasympathetic Gangliogenesis Requires Sprouty-Dependent Wnt Signals from Epithelial Progenitors
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DOI：
10.1016/j.devcel.2015.01.023
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发表时间：
2015-03-23
影响因子：
11.8
通讯作者：
Hoffman, Matthew P.
中科院分区：
文献类型：
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作者：
Knosp, Wendy M.;Knox, Sarah M.;Hoffman, Matthew P.
副交感神经支配对颌下腺的发育和再生至关重要。副交感神经节（PSG）来源于许旺细胞前体，其沿神经沿着迁移，分化成神经元，并在其靶组织内合并以形成神经节。然而，在前体分化成神经元后启动神经节发生的信号是未知的。我们发现，删除FGF信号传导的负调节因子Sprouty 1和Sprouty 2（Spry 1/2DKO），导致SMG中神经节发生、神经支配和角蛋白5阳性（K5+）上皮祖细胞的显著丧失。在这里，我们确定了由SMG中的K5+祖细胞产生的Wnt作为神经节发生的关键介质。Wnt信号传导增加PSG神经元的存活和增殖，并且抑制Wnt信号传导破坏神经节发生和器官神经支配。激活Wnt信号传导和减少FGF基因剂量挽救了Spry 1/2DKO SMG和胰腺中的神经节发生和神经支配。因此，K5+祖细胞产生Wnt信号以建立器官神经支配和祖细胞维持所需的PSG-上皮通讯。
Parasympathetic innervation is critical for submandibular gland (SMG) development and regeneration. Parasympathetic ganglia (PSG) are derived from Schwann cell precursors that migrate along nerves, differentiate into neurons, and coalesce within their target tissue to form ganglia. However, signals that initiate gangliogenesis after the precursors differentiate into neurons are unknown. We found that deleting negative regulators of FGF signaling, Sprouty1 and Sprouty2 (Spry1/2DKO), resulted in a striking loss of gangliogenesis, innervation, and keratin 5-positive (K5+) epithelial progenitors in the SMG. Here we identify Wnts produced by K5+ progenitors in the SMG as key mediators of gangliogenesis. Wnt signaling increases survival and proliferation of PSG neurons, and inhibiting Wnt signaling disrupts gangliogenesis and organ innervation. Activating Wnt signaling and reducing FGF gene dosage rescues gangliogenesis and innervation in both the Spry1/2DKO SMG and pancreas. Thus, K5+ progenitors produce Wnt signals to establish the PSG-epithelial communication required for organ innervation and progenitor cell maintenance.