The Tumor Suppressor Adenomatous Polyposis Coli (apc) Is Required for Neural Crest-Dependent Craniofacial Development in Zebrafish.

Neural crest (NC) is a unique vertebrate cell type arising from the border of the neural plate and epidermis that gives rise to diverse tissues along the entire body axis. Roberto Mayor and colleagues have made major contributions to our understanding of NC induction, delamination, and migration. We report that a truncating mutation of the classical tumor suppressor Adenomatous Polyposis Coli (apc) disrupts craniofacial development in zebrafish larvae, with a marked reduction in the cranial neural crest (CNC) cells that contribute to mandibular and hyoid pharyngeal arches. While the mechanism is not yet clear, the altered expression of signaling molecules that guide CNC migration could underlie this phenotype. For example, apcmcr/mcr larvae express substantially higher levels of complement c3, which Mayor and colleagues showed impairs CNC cell migration when overexpressed. However, we also observe reduction in stroma-derived factor 1 (sdf1/cxcl12), which is required for CNC migration into the head. Consistent with our previous work showing that APC directly enhances the activity of glycogen synthase kinase 3 (GSK-3) and, independently, that GSK-3 phosphorylates multiple core mRNA splicing factors, we identify 340 mRNA splicing variations in apc mutant zebrafish, including a splice variant that deletes a conserved domain in semaphorin 3f (sema3f), an axonal guidance molecule and a known regulator of CNC migration. Here, we discuss potential roles for apc in CNC development in the context of some of the seminal findings of Mayor and colleagues.

神经嵴（NC）是一种独特的脊椎动物细胞类型，源自神经板和表皮的边界，可沿整个体轴产生多种组织。罗伯托·马约尔及其同事对我们理解神经嵴的诱导、分层和迁移做出了重大贡献。我们报道，经典肿瘤抑制因子腺瘤性息肉病 coli（apc）的截短突变破坏了斑马鱼幼体的颅面发育，对构成下颌和舌骨咽弓有贡献的颅神经嵴（CNC）细胞显著减少。虽然机制尚不清楚，但引导CNC迁移的信号分子表达改变可能是这种表型的基础。例如，apcmcr/mcr幼体表达的补体C3水平显著升高，马约尔及其同事表明补体C3过表达时会损害CNC细胞迁移。然而，我们也观察到基质衍生因子1（sdf1/cxcl12）减少，而它是CNC迁移到头部所必需的。与我们之前的研究结果一致，即APC直接增强糖原合成酶激酶3（GSK - 3）的活性，并且独立地，GSK - 3使多个核心mRNA剪接因子磷酸化，我们在apc突变斑马鱼中鉴定出340种mRNA剪接变异，包括一种剪接变体，它缺失了信号素3f（sema3f）中的一个保守结构域，信号素3f是一种轴突导向分子，也是已知的CNC迁移调节因子。在此，我们结合马约尔及其同事的一些重要发现，讨论apc在CNC发育中的潜在作用。