Mechanisms underpinning human neocortical development and neurodevelopmental disorders: The novel role of Extracellular Matrix.

支持人类新皮质发育和神经发育障碍的机制：细胞外基质的新作用。

• 批准号: MR/S025065/1
• 负责人: Katherine Long
• 金额: $ 182.43万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2019
• 资助国家: 英国
• 起止时间: 2019 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FS025065%2F1
• 关键词: Mechanisms; underpinning; human; neocortical; development

The human neocortex is the seat of many of the higher cognitive functions that make us human. These include our memory, speech and advanced learning. Our neocortex has greatly expanded during evolution, resulting in an increase in the number of nerve cells (neurons) within it, and an increase in overall size. This expansion was accompanied by folding of the cortical surface, which gives the brain its wrinkled appearance and allowed the expansion of the cortical surface area within the confinement of the developing skull.Despite their functional importance, we know relatively little about how these folds are formed in development. What is known, is that these cortical folds are very similar between individuals, so much so, that the largest folds are almost identical. This suggests that the formation of the correct number of folds in the correct location is important for their function. In fact, cognitive defects are observed in various neurodevelopmental disorders that result in abnormal cortical folding, i.e. disorders with too much folding, such as polymicrogyria, and not enough folding, such as lissencephaly, suggesting that the regulation of folding during development is crucial.My work has shown that the extracellular matrix (ECM), the proteins that surround cells in a tissue, has a key role in regulating how cortical folds form. Manipulating the ECM in tissue slices of human fetal neocortex kept in culture induced folding of the cortical plate. This ECM-induced folding was reduced or delayed in neocortex samples with specific neurodevelopmental defects, such as Down syndrome and prenatal methamphetamine exposure. Both of these disorders are known to have developmental delays or defects in the neocortex, which are currently not fully understood. The ECM-induced folding of human neocortex explants can now be used to probe these disorders and others. This is particularly important for the disorders that currently lack suitable animal models. Of these, the most relevant are the disorders that alter cortical folding, as many of the model systems used to study neocortex development naturally lack folding (such as mice). I predict that there are many more functions of ECM in human neocortex development, folding and related neurodevelopmental disorders. Therefore, the overall aim of my proposal is to investigate how ECM regulates human neocortex development and its related disorders, using the novel human neocortex explant systems I have developed.The first aim of my proposal is to use my ECM-folding assay to investigate the function of ECM genes that have already been linked to specific neurodevelopmental disorders in patients. Two candidates are the ECM protein perlecan, and the ECM receptor dystrogylcan. Both of these genes are linked to the folding disorder lissencehpaly.The second aim is to examine the exact composition of the ECM within the developing human neocortex. There is currently very little data on what ECM is expressed in the human neocortex, when it is expressed and where it is located. This is vital information that will help us understand not only the normal function of the ECM in human neocortex development, but also help understand and predict how mutations in ECM genes led to neurodevelopmental defects.The third aim is to test the function of ECM proteins in human neocortex development, using the human neocortex explant culture system and ECM-folding assay. This will increase our understanding of how ECM regulates the development and folding of the cortex, and its dysregulation.This fellowship funding would allow me to set up my independent research group, addressing these fundamental questions of how the human neocortex develops and how this development goes awry in developmental disorders. It will uncover the role of the ECM in both of these processes, and increase our knowledge and understanding of the normal neocortex development and folding, and the dysregulation seen in related disorders.

人类的新皮层是许多高级认知功能的所在地，这些功能使我们成为人类。这些包括我们的记忆、语言和高级学习能力。在进化过程中，我们的新皮质大大扩展，导致其中的神经细胞（神经元）数量增加，整体尺寸增加。这种扩张伴随着皮层表面的折叠，这使大脑呈现出褶皱的外观，并允许在发育中的颅骨的限制内皮层表面积的扩张。尽管它们的功能很重要，但我们对这些褶皱在发育过程中是如何形成的知之甚少。我们所知道的是，这些皮质褶皱在个体之间非常相似，以至于最大的褶皱几乎是相同的。这表明，在正确的位置形成正确数量的褶皱对它们的功能很重要。事实上，在各种神经发育障碍中都观察到认知缺陷导致皮层折叠异常，即折叠过多的疾病，如多小回症，而折叠不足的疾病，如无脑畸形，这表明在发育过程中折叠的调节是至关重要的。我的工作表明，细胞外基质（ECM），即组织中包围细胞的蛋白质，在调节皮层褶皱的形成方面起着关键作用。对培养的人胎儿新皮层组织切片进行ECM处理，可诱导皮层板折叠。在具有特定神经发育缺陷（如唐氏综合症和产前甲基苯丙胺暴露）的新皮层样本中，这种ecm诱导的折叠减少或延迟。已知这两种疾病都有发育迟缓或新皮层缺陷，目前尚未完全了解。ecm诱导的人类新皮质外植体折叠现在可以用来探测这些疾病和其他疾病。这对于目前缺乏合适动物模型的疾病尤其重要。其中，最相关的是改变皮层折叠的疾病，因为许多用于研究新皮层发育的模型系统自然缺乏折叠（如小鼠）。我预测ECM在人类新皮层发育、折叠和相关神经发育障碍中有更多的功能。因此，我建议的总体目标是研究ECM如何调节人类新皮层发育及其相关疾病，使用我开发的新型人类新皮层外植体系统。我提议的第一个目标是使用我的ECM折叠试验来研究已经与患者特定神经发育障碍相关的ECM基因的功能。两种候选物质是ECM蛋白透蛋白和ECM受体肌营养不良聚糖。这两种基因都与无脑性折叠障碍有关。第二个目的是检查发育中的人类新皮层内脑外基质的确切组成。目前关于ECM在人类新皮层中表达的内容、表达时间和位置的数据非常少。这一重要信息不仅有助于我们理解ECM在人类新皮层发育中的正常功能，还有助于理解和预测ECM基因突变如何导致神经发育缺陷。第三个目的是利用人新皮层外植体培养系统和ECM折叠实验，测试ECM蛋白在人新皮层发育中的功能。这将增加我们对脑外基质如何调节皮层的发育和折叠及其失调的理解。这笔奖学金资金将允许我建立自己的独立研究小组，研究人类新皮层是如何发育的以及这种发育在发育障碍中是如何出错的这些基本问题。它将揭示ECM在这两个过程中的作用，并增加我们对正常新皮层发育和折叠的认识和理解，以及在相关疾病中看到的失调。

项目成果

The Role of the Extracellular Matrix in Neural Progenitor Cell Proliferation and Cortical Folding During Human Neocortex Development.

• DOI: 10.3389/fncel.2021.804649
• 发表时间: 2021
• 期刊: Frontiers in cellular neuroscience
• 影响因子: 5.3
• 作者: Long KR;Huttner WB
• 通讯作者: Huttner WB

Cryogel scaffolds: soft and easy to use tools for neural tissue culture.

• DOI: 10.4103/1673-5374.335156
• 发表时间: 2022-09
• 期刊: Neural regeneration research
• 影响因子: 6.1
• 作者: Newland B;Long KR
• 通讯作者: Long KR

In preprints: shaping the developing human brain

预印本：塑造发育中的人类大脑

• DOI: 10.1242/dev.202567
• 发表时间: 2023
• 期刊: Development
• 影响因子: 4.6
• 作者: Massimo M

Neurometabolite mapping highlights elevated myo-inositol profiles within the developing brain in down syndrome.

• DOI: 10.1016/j.nbd.2021.105316
• 发表时间: 2021-06
• 期刊: Neurobiology of disease
• 影响因子: 6.1
• 作者: Patkee PA;Baburamani AA;Long KR;Dimitrova R;Ciarrusta J;Allsop J;Hughes E;Kangas J;McAlonan GM;Rutherford MA;De Vita E
• 通讯作者: De Vita E

Neurometabolite Mapping Highlights Elevated Myo-inositol Profiles within the Developing Brain in Down Syndrome

神经代谢图谱突显唐氏综合症大脑发育中肌醇谱的升高

• DOI: 10.1101/2020.07.20.211805
• 发表时间: 2020
• 作者: Patkee P