The transcription factor Hypermethylated in Cancer 1 (HIC1) is associated with both tumorigenesis and the complex human developmental disorder Miller-Dieker Syndrome. While many studies have characterized HIC1 as a tumor suppressor, HIC1 function in development is less understood. Loss-of-function mouse alleles show embryonic lethality accompanied with developmental defects, including craniofacial abnormalities that are reminiscent of human Miller-Dieker Syndrome patients. However, the tissue origin of the defects has not been reported. In this study, we use the power of the Xenopus laevis model system to explore Hic1 function in early development. We show that hic1 mRNA is expressed throughout early Xenopus development and has a spatial distribution within the neural plate border and in migrating neural crest cells in branchial arches. Targeted manipulation of hic1 levels in the dorsal ectoderm that gives rise to neural and neural crest tissues reveals that both overexpression and knockdown of hic1 result in craniofacial defects with malformations of the craniofacial cartilages. Neural crest specification is not affected by altered hic1 levels, but migration of the cranial neural crest is impaired both in vivo and in tissue explants. Mechanistically, we find that Hic1 regulates cadherin expression profiles and canonical Wnt signaling. Taken together, these results identify Hic1 as a novel regulator of the canonical Wnt pathway during neural crest migration.

癌症1（HIC1）中的高甲基化转录因子与肿瘤发生和复杂的人类发育疾病Miller-Dieker综合征相关。尽管许多研究已将HIC1表征为肿瘤抑制因子，但对HIC1在发育中的功能了解甚少。功能丧失的小鼠等位基因显示出胚胎致死性，并伴有发育缺陷，包括颅面异常，使人联想到人类Miller-Dieker综合征患者。然而，尚未报道缺陷的组织起源。在这项研究中，我们使用非洲爪蟾模型系统的功能来探索Hic1在早期开发中的功能。我们显示hic1 mRNA在整个非洲爪蟾早期表达发育并在神经板边界内和branch弓中的神经c细胞迁移中具有空间分布。有针对性地操纵背外皮中的hic1水平会引起神经和神经neural组织的发育，这表明hic1的过表达和基因敲低均会导致颅面缺陷和颅面软骨畸形。神经ic的规格不受hic1水平改变的影响，但在体内和体外都影响颅神经neural的迁移和组织外植体中。从机理上讲，我们发现Hic1调节钙黏着蛋白表达谱和经典Wnt信号传导。两者合计，这些结果确定Hic1是神经c迁移过程中经典Wnt通路的新型调节剂。