9514552 Birren The mammalian nervous system is made up of an astonishingly large number different nerve cells (neurons) which interact to permit thought, movement and the control of bodily functions. The generation of this enormous cellular diversity is one of the central issues of developmental neurobiology. We know that the many different classes of neurons arise from a relatively small number of undifferentiated precursor cells in the mammalian embryo. The goal of this project is to understand how these precursor cells respond to signals in their local embryonic environment to develop into the correct type of neuron for a given area of the embryo. The peripheral nervous system provides an excellent system for this study. Evidence from other laboratories has suggested that the enteric neurons that control the function of the mammalian gut are very closely related to the sympathetic neurons that control involuntary functions such as heart rate. In fact, it has been suggested that these two neuronal lineages arise from a common embryonic precursor cell. We plan to directly test the idea that the precursor cells that normally develop into sympathetic neurons have the capacity to develop into enteric neurons when provided with the appropriate embryonic signals. Likewise, we will investigate whether enteric precursor cells can develop into sympathetic neurons. We will also test the idea that as these cells respond to signals and follow one of these differentiation pathways that they lose the ability to respond to signals from the other lineage. This will permit us to define the developmental time that multipotent precursor cells become restricted to specific cell lineages. Finally, we will seek to understand the nature of the signals that direct the precursor down one or the other neuronal lineage. We will study the distribution of neurotrophin receptors in the developing sympathetic and enteric nervous system. These receptors comprise a family of proteins that play a role in the de velopment of many different types of neurons. We will test the possibility that one of the members of this receptor family is directly responsible for lineage decisions in the sympathetic nervous system. We will do this by introducing the expression of this receptor into enteric and sympathetic precursor cells at early developmental stages and asking if we can observe alterations in the type of neurons developing from the precursors. These experiments will provide important information on how the early embryo controls the development of different cell types from uncommitted precursor cells. Normal development of the mammalian embryo requires that many such lineage decisions be carried out in a very precise manner. Our studies will shed light on the mechanisms that control these developmental patterns.
