Role of Complement in Neural Crest migration and craniofacial development

颅面部疾病是婴儿死亡的主要原因，具有严重的终生后果，对儿童和父母都是毁灭性的。颅面畸形通常被认为是面部潜在结构的异常，如骨骼和软骨发育异常。面部骨骼和软骨起源于一种名为神经脊的细胞群，在胚胎发育过程中，神经脊从头部后部迁移形成面部。因此，颅面部疾病通常被归因于神经脊发育问题。有许多种类的颅面畸形都有遗传起源，但只有几个案例中发现了突变基因。此外，只有在极少数病例中，才知道受影响基因的功能。在这个项目中，我们建议使用易于进行基因解剖的动物模型来研究可能与颅面畸形有关的基因。该项目产生的数据将直接用于后续研究，以测试等同基因的突变是否会导致人类头面部畸形。为了发现这些新基因，我们从免疫系统等对细胞迁移有了更好理解的其他系统中推断出了知识。我们的初步数据表明，一种特征良好的免疫反应途径，称为补体，可能在神经脊迁移中发挥关键作用。补体级联被免疫系统用来控制感染和摧毁微生物。我们的观察表明，补体级联的特定元件的突变会导致神经脊迁移的严重缺陷。在这个项目中，我们建议确定这些因素控制神经脊发育的细胞和分子机制。尽管补体缺乏在患者中是一个相对常见的问题，但这个系统在胚胎发育中的作用被完全忽视，更不用说在头面部疾病中了。这将是第一次在胚胎中出现任何血液或血管之前，在发育的早期阶段涉及补体因子。了解补体在神经脊迁移中的作用，将为了解某些先天性颅面缺损的起源奠定基础，并为制定预防策略和修复治疗提供可能。重要的是，补体系统在正常头面部形成中发挥作用的论证将在卫生政策中产生深远影响。我们的研究结果可能表明，孕妇在怀孕早期应该避免补体抑制剂治疗(以治疗自身免疫性疾病)。这可能会给儿童带来毁灭性的后果，相当于过去使用沙利度胺。

Craniofacial disorders are a primary cause of infant mortality and have serious lifetime consequences, devastating for both children and parents. Craniofacial malformations are usually recognized as abnormalities in the underlying structure of the face, such as anomalies in bone and cartilage development. Facial bones and cartilages originate from a cell population called the neural crest, which migrates from the back of the head to form the face during embryonic development. Therefore, craniofacial disorders are usually attributed to problems in neural crest development. There is a large variety of craniofacial anomalies which have a genetic origin but in only a few cases have the mutated genes been identified. Moreover, only in an extremely small proportion of these cases is the function of the affected gene known. In this project we propose to use animal models that are amenable to genetic dissection to study genes that are potentially involved in craniofacial malformations. The data generated in this project will be directly used in subsequent research to test whether mutations in equivalent genes lead to craniofacial anomalies in humans. In order to find these new genes we have extrapolated knowledge from other systems in which cell migration is better understood, as the immune system. Our preliminary data suggests that a well characterised immune response pathway, called complement, may play a key role in neural crest migration. The complement cascade is used by the immune system to control infections and destroy microbes. Our observations show that mutations in specific elements of the complement cascade lead to dramatic defects on neural crest migration. In this project we propose to identify the cellular and molecular mechanisms by which these factors control neural crest development. In spite of complement deficiencies being a relatively common problem in patients, the role of this system in embryonic development, let alone in craniofacial disorders, has been completely neglected. This will be the first time to implicate complement factors in the early phases of development, before any blood or vessels are present in the embryo. Understanding the role of complement in neural crest migration will be a prelude to understanding the origins of some congenital craniofacial defects, and will open the possibility to develop prevention strategies and repair therapies. Importantly, the demostration that the complement system plays a role in normal cranofacial formation will have a profound impact in health policy. The results from our research may suggest that pregnant women should avoid complement inhibitors treatments (to treat autoimmune diseases) during early gestation. These could have devastating consequences for the child, equivalent to the use of thalidomide in the past.