The segregation of neurons and axons into compartments is a fundamental aspect of the organization of the CNS. Research in the mouse is proposed to investigate: 1) the prenatal cellular events responsible for the laminar stratification of Purkinje and roof nuclear neurons in the cerebellum, and 2) the early postnatal events leading to the recently discovered non-laminar compartmentation in the striatum, described as a patch-matrix organization. In both structures, we hypothesize that the earliest generated cells form coherent aggregates with which later migrating cells interact according to simple rules, the outcome of which creates the structural foundation for all subsequent developmental events. Study of the migration and segregation of neuron populations with tritiated thymidine autoradiography and Golgi methods form a common basis for the research program on the two structures. Also in both structures, the distribution of radial glial processes stained with a monoclonal antibody will be studied with respect to their potential role in guiding neuron sets to their respective domains. In the striatum, antibodies to the enzyme, tyrosine hydroxylase, will be used to identify the incipient compartments. In the cerebellum, we will undertake an analysis of the axon systems present at the time of early morphogenetic events. This work will involve the use of immunocytochemistry with monoclonal antibodies that recognize either all axons or selected subsets of fibers. Assessment of extrinsic axon origins through a retrograde tracer analysis will be performed in the fetal rat because of its larger size. Because Purkinje cells and fiber strata become anomalously inverted in the reeler mutant mouse, ontogenetic studies planned in this animal are expected to elucidate the normal interactions between migrating cells and early developing axon systems. The results of the proposed research program should help identify general principles of elemental neuronal compartmentation. Progress toward this goal is essential for an understanding of certain devastating neurological diseases that involve defects in basic neuronal organization.
