Complement as a novel regulator of Wnt signalling during craniofacial development

作为颅面发育过程中 Wnt 信号传导的新型调节剂的补充

• 批准号: MR/M010465/1
• 负责人: Roberto Mayor
• 金额: $ 52.56万
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM010465%2F1
• 关键词: Complement; novel; regulator; Wnt; signalling

According to the World Health Organization, birth defects affect one in every 33 infants, resulting in approximately 3.2 million disabilities every year (http://www.who.int/mediacentre/factsheets/fs370/en/). Deformations of the head and face, termed craniofacial defects, make up one third of this total. Such anomalies typically result from faulty formation of the bones and cartilage in this region. It is important, therefore, that we understand how these structures are normally formed if we want to devise effective ways to treat or prevent such defects from occurring. To do that, we have turned our attention to a group of embryonic cells called the neural crest. The neural crest is a population of cells found early in the life of an embryo. Shortly after their formation, these cells move through the embryo and establish the tissues that will eventually become mature structures such as ribs, muscles, nerves and many of the components of the face and neck. In order to build these structures in the correct sizes and shapes, the movements and behaviour of the neural crest cells must be precisely controlled. When this control fails malformations of these structures often results. Our aim is to understand the way in which this control operates. Some clues have come from the field of genetics. Indeed, a number of craniofacial anomalies are known to have a genetic origin, but in only a few cases have the mutated genes been identified. One such gene is responsible for producing a chemical signal called Wnt, which is critical for the formation of neural crest cells. For embryos to develop properly it is essential that Wnt signaling occurs at the correct times and places, yet exactly how this is achieved in the embryo remains a mystery. Our preliminary work has revealed an unexpected way in which this might happen. It seems that a group of proteins normally involved in immunity may play a critical role. The complement cascade, as they are collectively known, is responsible for killing foreign pathogens and monitoring self versus non-self recognition in the immune system. We have found that if we block the cascade's function in young embryos neural crest formation and migration are defective. Our data indicate that this is due to a deficiency in Wnt signalling. Furthemore, a recent publication shows that complement deficiencies lead to dramatic craniofacial defects (Rooryck et al (2011) Nat Genet 43, 197). These findings suggest that the complement cascade is important for normal craniofacial development and may shed light on causes of craniofacial defects that remain poorly understood. Consequently, this work may have a profound impact on health policy. For example, the results from our research may suggest that pregnant women should avoid certain treatments for autoimmune disorders that target the complement cascade, as these could have devastating consequences for the child, equivalent to the use of thalidomide in the past.

据世界卫生组织称，每33名婴儿中就有一名患有出生缺陷，每年造成约320万人残疾（http：//www.who.int/mediacentre/factsheets/fs370/en/）。头面部畸形，称为颅面缺陷，占总数的三分之一。这种异常通常是由于该区域的骨骼和软骨形成不良造成的。因此，如果我们想要设计有效的方法来治疗或防止此类缺陷的发生，那么了解这些结构通常是如何形成的就很重要了。为了做到这一点，我们将注意力转向了一组称为神经嵴的胚胎细胞。神经嵴是在胚胎生命早期发现的细胞群。在它们形成后不久，这些细胞在胚胎中移动并建立最终成为成熟结构的组织，如肋骨，肌肉，神经和面部和颈部的许多组成部分。为了以正确的大小和形状构建这些结构，必须精确控制神经嵴细胞的运动和行为。当这种控制失败时，往往会导致这些结构的畸形。我们的目的是了解这种控制的运作方式。一些线索来自遗传学领域。事实上，许多颅面畸形已知有遗传起源，但只有在少数情况下，突变的基因被确定。其中一个基因负责产生一种称为Wnt的化学信号，这对神经嵴细胞的形成至关重要。为了使胚胎正常发育，Wnt信号在正确的时间和地点发生是至关重要的，但这在胚胎中是如何实现的仍然是一个谜。我们的初步工作揭示了这可能发生的意想不到的方式。似乎一组通常参与免疫的蛋白质可能起着关键作用。补体级联，因为它们被统称为，负责杀死外来病原体和监测免疫系统中的自我与非自我识别。我们发现，如果我们阻止该级联反应在年轻胚胎中的功能，神经嵴的形成和迁移就会有缺陷。我们的数据表明，这是由于Wnt信号传导的缺陷。此外，最近的出版物显示，补体缺乏导致显著的颅面缺陷（Rooryck等人（2011）Nat Genet 43，197）。这些发现表明，补体级联反应是重要的正常颅面发育，并可能揭示颅面缺陷的原因仍然知之甚少。因此，这项工作可能对卫生政策产生深远影响。例如，我们的研究结果可能表明，孕妇应该避免针对补体级联反应的某些自身免疫性疾病的治疗，因为这些治疗可能会对孩子造成毁灭性的后果，相当于过去使用沙利度胺。

项目成果

Cadherin Switch during EMT in Neural Crest Cells Leads to Contact Inhibition of Locomotion via Repolarization of Forces.

神经嵴细胞 EMT 期间的钙粘蛋白开关通过力的复极化导致运动的接触抑制。

• DOI: 10.1016/j.devcel.2015.06.012
• 发表时间: 2015-08-24
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Scarpa E;Szabó A;Bibonne A;Theveneau E;Parsons M;Mayor R
• 通讯作者: Mayor R

Forcing contact inhibition of locomotion.

强迫接触运动。

• DOI: 10.1016/j.tcb.2015.05.001
• 发表时间: 2015-07
• 期刊: Trends in cell biology
• 影响因子: 19
• 作者: Roycroft A;Mayor R
• 通讯作者: Mayor R

Molecular basis of contact inhibition of locomotion.

• DOI: 10.1007/s00018-015-2090-0
• 发表时间: 2016-03
• 期刊: Cellular and molecular life sciences : CMLS
• 作者: Roycroft A;Mayor R
• 通讯作者: Mayor R

Collective cell migration in development.

• DOI: 10.1083/jcb.201508047
• 发表时间: 2016-01-18
• 期刊: The Journal of cell biology
• 作者: Scarpa E;Mayor R
• 通讯作者: Mayor R

Chemotaxis during neural crest migration.

• DOI: 10.1016/j.semcdb.2016.01.031
• 发表时间: 2016-07
• 期刊: Seminars in cell & developmental biology
• 影响因子: 7.3
• 作者: Adam Shellard;R. Mayor