Signal integration and interpretation during neural development

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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.