Signal integration and interpretation during neural development

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，以及这些信息是如何翻译的，以便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，细胞可以形成任何类型的神经细胞，但作为对化学信号的反应，它们决定成为一种特定的类型。不同的信号从不同的方向传播，提供了可以被认为是正在发育的神经系统的3D地图中的坐标。细胞通过解释它们所接触到的信号的性质和数量来决定成为哪种类型的神经。虽然对单个信号的活动已经有了很多了解，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合适，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。这些研究将深入了解不同类型的神经是如何在胚胎发育过程中形成的，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。神经细胞来源于增殖的祖细胞池，这些祖细胞沿着神经管的背侧-腹侧(DV)和前后(AP)轴以固定的顺序排列。沿DV轴以梯度方式作用的信号以及沿AP轴作用的信号对于细胞命运的指定非常重要。这些信号被称为形态原，是神经细胞命运指定所必需的。形态原具有两个重要特征：(A)它以浓度依赖的方式发挥作用，在接收细胞场中引发不同的反应；(B)它在组织中传播，在远离其来源的地方发挥作用。Shh已知可以控制特定基因的表达，这些基因可以诱导一系列导致特定神经细胞类型的事件。然而，对Shh反应产生的神经元的类型也取决于神经系统的区域，例如，位于后脑和脊髓类似位置的细胞产生不同类型的神经元。为了了解这是如何实现的，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基于胚胎干细胞分化的系统，在这个系统中，我们可以控制和指导培养皿中特定神经类型的分化。我们将使用这一强大的系统和最新的技术，如基因组分析来确定分子机制。这项研究的发现将提高我们对神经系统发育以及多能干细胞向特定神经细胞类型分化方案的理解。这一发现可能会对干细胞和系统生物学日益增长的领域产生重要影响。

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.