A Wnt/Notch/Pax7 signaling network supports tissue integrity in tongue development
A Wnt/Notch/Pax7 signaling network supports tissue integrity in tongue development
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Wnt/Notch/Pax7 信号网络支持舌头发育中的组织完整性
DOI：
10.1074/jbc.m117.789438
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发表时间：
2017
影响因子：
4.8
通讯作者：
Zhang Zunyi
中科院分区：
文献类型：
--
作者：
Zhu Xiao-Jing;Yuan Xueyan;Wang Min;Fang Yukun;Liu Yudong;Zhang Xiaoyun;Yang Xueqin;Li Yan;Li Jianying;Li Feixue;Dai Zhong-Min;Qiu Mengsheng;Zhang Ze;Zhang Zunyi
舌头是参与人类食物摄入和言语的主要结构之一。舌畸形如无舌症、小舌症和舌系带过短是先天性出生缺陷，极大地影响个体的生活质量。然而，确保组织形态形成以形成功能性舌的组织-组织相互作用的分子基础在很大程度上仍然未知。在这里，我们表明，ShhCre介导的上皮缺失Wntless（Wls），细胞内Wnt运输的关键调节因子，导致小鼠舌发育不全。通过上皮细胞中Wls缺失破坏上皮Wnt产生导致舌表皮分层失败，并且在发育中的小鼠舌中固有层和下层上级纵肌丢失。这些缺陷的表型导致减少上皮基底细胞阳性的基础表皮标志物蛋白p63和受损的结缔组织和配对框3（Pax 3）和Pax 7阳性的肌肉祖细胞的增殖和分化。我们还发现，上皮Wnt的产生是激活Notch信号通路所必需的，Notch信号通路促进肌源性祖细胞的增殖。Notch信号反过来负调控Wnt信号在舌形态发生。我们进一步表明Pax 7是胚胎舌中的直接Notch靶基因。总之，我们的研究结果表明，舌上皮信号在支持舌发育过程中固有层和肌肉组织的完整性方面发挥着关键作用，并且Wnt/Notch/Pax 7遗传层次参与了这种发育。
The tongue is one of the major structures involved in human food intake and speech. Tongue malformations such as aglossia, microglossia, and ankyloglossia are congenital birth defects, greatly affecting individuals' quality of life. However, the molecular basis of the tissue-tissue interactions that ensure tissue morphogenesis to form a functional tongue remains largely unknown. Here we show that ShhCre-mediated epithelial deletion of Wntless (Wls), the key regulator for intracellular Wnt trafficking, leads to lingual hypoplasia in mice. Disruption of epithelial Wnt production by Wls deletion in epithelial cells led to a failure in lingual epidermal stratification and loss of the lamina propria and the underlying superior longitudinal muscle in developing mouse tongues. These defective phenotypes resulted from a reduction in epithelial basal cells positive for the basal epidermal marker protein p63 and from impaired proliferation and differentiation in connective tissue and paired box 3 (Pax3)- and Pax7-positive muscle progenitor cells. We also found that epithelial Wnt production is required for activation of the Notch signaling pathway, which promotes proliferation of myogenic progenitor cells. Notch signaling in turn negatively regulated Wnt signaling during tongue morphogenesis. We further show that Pax7 is a direct Notch target gene in the embryonic tongue. In summary, our findings demonstrate a key role for the lingual epithelial signals in supporting the integrity of the lamina propria and muscular tissue during tongue development and that a Wnt/Notch/Pax7 genetic hierarchy is involved in this development.