Signal integration and interpretation during neural development

神经发育过程中的信号整合和解释

• 批准号: BB/J015539/1
• 负责人: James Briscoe
• 金额: $ 32.52万
• 依托单位: The Francis Crick Institute
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ015539%2F1
• 关键词: Signal; integration; interpretation; during; neural

An important question in biology is "how do cells know where they are within a tissue and how is this information translated so that they form the appropriate structures for their positions?" Our central nervous system (CNS) contains many different types of neural cells arranged and interconnected in a complex pattern. This is a consequence of early embryonic development when neural cells acquire their unique location and identity. Initially cells can form any neural cell type, but in response to chemical signals they make a decision to become a specific type. The various signals spread from different directions providing the coordinates in what can be thought of as a 3D map of the developing nervous system. Cells decide what type of nerve to become by interpreting the nature and amounts of signals to which they are exposed. While much has been learned about the activities of individual signals, how cells perceive multiple signals and integrate this information to make the appropriate neural cell types for the specific location is very poorly understood. Here we will tackle this problem by performing experiments in two parts of the CNS - the hindbrain and the spinal cord. These studies will provide insight into how different nerve types are made during embryonic development and may help explain how the ordered complexity of the CNS arises. Nerve cells arise from pools of proliferating progenitors that are arrayed in a stereotypic order along the dorsal-ventral (DV) and anterior-posterior (AP) axis of the neural tube. Signals that act in a gradient along the DV axis as well as signals that act along the AP axis are very important for cell fate specification. These signals are called morphogens and are necessary for neural cell fate specification. A morphogen has two important characteristics: (a) it functions in a concentration dependent manner to induce different responses in a field of receiving cells and (b) it spreads though a tissue to act at a distance from its source. Shh is known to control the expression of specific genes that induce a cascade of events that give rise to specific neuronal cell types. However the types of neurons are generated in response to Shh depend also the region of the nervous system, for example cells located at similar positions in the hindbrain and in the spinal cord produce different types of neurons. To understand how this is achieved we will identify how genes that encode the AP position (Hox genes) interact with Shh signaling. We have established a system, based on the differentiation of embryonic stem (ES) cells, in which we can control and direct the differentiation of specific neural types in a dish. We will use this powerful system with the latest technologies, such as genome analysis to identify the molecular mechanisms. The findings from this research will improve our understanding of nervous system development as well as the differentiation protocols of pluripotent stem cells to specific neuronal cell types. The findings are likely to have important implications for the growing fields of stem cell and systems biology.

生物学中的一个重要问题是“细胞如何知道它们在组织中的位置，以及如何翻译这些信息，使它们形成适合其位置的结构？“我们的中枢神经系统（CNS）包含许多不同类型的神经细胞，它们以复杂的模式排列和相互连接。这是早期胚胎发育的结果，当时神经细胞获得了它们独特的位置和身份。最初，细胞可以形成任何神经细胞类型，但为了响应化学信号，它们会决定成为特定类型。不同的信号从不同的方向传播，提供了可以被认为是发育中的神经系统的3D地图的坐标。细胞通过解释它们所暴露的信号的性质和数量来决定成为哪种类型的神经。虽然人们对单个信号的活动已经了解了很多，但细胞如何感知多个信号并整合这些信息以使特定位置的神经细胞类型变得合适，这一点仍然知之甚少。在这里，我们将通过在中枢神经系统的两个部分--后脑和脊髓--进行实验来解决这个问题。这些研究将提供对胚胎发育过程中不同神经类型是如何形成的深入了解，并可能有助于解释中枢神经系统的有序复杂性是如何产生的。神经细胞来源于沿着神经管的背腹（DV）和前后（AP）轴以刻板顺序排列的增殖祖细胞池。沿着DV轴以梯度作用的信号以及沿沿着AP轴作用的信号对于细胞命运规格是非常重要的。这些信号被称为形态发生素，是神经细胞命运特化所必需的。形态发生素具有两个重要的特征：（a）它以浓度依赖性方式起作用，以在接受细胞的区域中诱导不同的反应，以及（B）它通过组织扩散，以在距其来源一定距离处起作用。已知Shh控制特定基因的表达，这些基因诱导级联事件，从而产生特定的神经元细胞类型。然而，响应于Shh产生的神经元的类型也取决于神经系统的区域，例如位于后脑和脊髓中相似位置的细胞产生不同类型的神经元。为了理解这是如何实现的，我们将确定编码AP位置的基因（Hox基因）如何与Shh信号相互作用。我们已经建立了一个系统，基于胚胎干（ES）细胞的分化，在其中我们可以控制和指导特定神经类型的分化。我们将使用这个强大的系统与最新的技术，如基因组分析，以确定分子机制。这项研究的发现将提高我们对神经系统发育的理解，以及多能干细胞向特定神经细胞类型的分化方案。这些发现可能对干细胞和系统生物学的发展领域产生重要影响。

项目成果

Human axial progenitors generate trunk neural crest cells in vitro.

• DOI: 10.7554/elife.35786
• 发表时间: 2018-08-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Frith TJ;Granata I;Wind M;Stout E;Thompson O;Neumann K;Stavish D;Heath PR;Ortmann D;Hackland JO;Anastassiadis K;Gouti M;Briscoe J;Wilson V;Johnson SL;Placzek M;Guarracino MR;Andrews PW;Tsakiridis A
• 通讯作者: Tsakiridis A

Nervous System Regionalization Entails Axial Allocation before Neural Differentiation.

• DOI: 10.1016/j.cell.2018.09.040
• 发表时间: 2018-11-01
• 期刊: Cell
• 影响因子: 64.5
• 作者: Metzis V;Steinhauser S;Pakanavicius E;Gouti M;Stamataki D;Ivanovitch K;Watson T;Rayon T;Mousavy Gharavy SN;Lovell-Badge R;Luscombe NM;Briscoe J
• 通讯作者: Briscoe J

Sonic hedgehog in vertebrate neural tube development

脊椎动物神经管发育中的音速刺猬

• DOI: 10.1387/ijdb.170293jb
• 发表时间: 2018
• 期刊: The International Journal of Developmental Biology
• 作者: Placzek M

G protein-coupled receptors control the sensitivity of cells to the morphogen Sonic Hedgehog.

• DOI: 10.1126/scisignal.aao5749
• 发表时间: 2018-02-06
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Pusapati GV;Kong JH;Patel BB;Gouti M;Sagner A;Sircar R;Luchetti G;Ingham PW;Briscoe J;Rohatgi R
• 通讯作者: Rohatgi R

A Gene Regulatory Network Balances Neural and Mesoderm Specification during Vertebrate Trunk Development.

• DOI: 10.1016/j.devcel.2017.04.002
• 发表时间: 2017-05-08
• 期刊: Developmental cell
• 影响因子: 11.8
• 作者: Gouti M;Delile J;Stamataki D;Wymeersch FJ;Huang Y;Kleinjung J;Wilson V;Briscoe J
• 通讯作者: Briscoe J