Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis
Disrupting hedgehog and WNT signaling interactions promotes cleft lip pathogenesis
复制标题
DOI：
10.1172/jci72688
复制
发表时间：
2014-04-01
影响因子：
15.9
通讯作者：
Trainor, Paul A.
中科院分区：
文献类型：
--
作者：
Kurosaka, Hiroshi;Iulianella, Angelo;Trainor, Paul A.
唇裂是颅颌面部最常见的先天性畸形之一，其发生与面突发育和融合障碍有关。许多基因被认为是参与这种疾病的病因，但是，我们的理解唇裂的发病机制仍然不完整。在本研究中，我们发现了音刺猬（SHH）信号在唇融合过程中的作用。携带刺猬酰基转移酶（Hhat）和patchedi（Ptch 1）复合突变的小鼠在额鼻发育过程中表现出SHH梯度的扰动，这导致了发育不全的鼻突生长，上皮接缝持久性和唇裂。进一步的研究表明，增强的SHH信号通过促进编码WNT抑制剂的基因的表达来限制lambd.oid.al区域中的典型WNT信号。此外，典型的WNT信号的减少扰乱了p63/干扰素调节因子6（p63/IRF 6）信号，导致增殖增加和细胞死亡减少，这是随后的上皮缝和唇裂的持久性。与我们的结果一致，突变。在患有唇裂的小鼠和人类中已经鉴定出破坏SHH和WNT信号传导的基因。总的来说，我们的数据表明，改变SHH信号有助于唇裂的病因和发病机制，通过拮抗与其他基因调控网络，包括经典的WNT和p63/IRF 6信号通路的相互作用。
Cleft lip, which results from impaired facial process growth and fusion, is one of the most common craniofacial birth defects. Many genes are known to be involved in the etiology of this disorder; however, our understanding of cleft lip pathogenesis remains incomplete. In the present study, we uncovered a role for sonic hedgehog (SHH) signaling during lip fusion. Mice carrying compound mutations in hedgehog acyltransferase (Hhat) and patchedi (Ptch1) exhibited perturbations in the SHH gradient during frontonasal development, which led to hypoplastic nasal process outgrowth, epithelial seam persistence, and cleft lip. Further investigation revealed that enhanced SHH signaling restricts canonical WNT signaling in the lambd.oid.al region by promoting expression of genes encoding WNT inhibitors. Moreover, reduction of canonical WNT signaling perturbed p63/interferon regulatory factor 6 (p63/IRF6) signaling, resulting in increased proliferation and decreased cell death, which was followed by persistence of the epithelial seam and cleft lip. Consistent with our results, mutations in. genes that disrupt SHH and WNT signaling have been identified in both mice and humans with cleft lip. Collectively, our data illustrate that altered SHH signaling contributes to the etiology and pathogenesis of cleft lip through antagonistic interactions with other gene regulatory networks, including the canonical WNT and p63/IRF6 signaling pathways.