ABSTRACT IBN-9723934 RANSCHT Brain function critically depends on the wiring of nerve fibers into a complex neuronal network. This network is established during embryonic development as neurons extend processes, called axons, that carry on their distal tip a mobile structure, the growth cone. The growth cones of each neuron type sense cues in their cellular environment to navigate to, recognize and form functional contacts with specific target cells, such as other neurons or effector organs such as muscle, glands or skin. In order to recognize the guidance cues in their environment and seek out the proper cells to contact, growth cones explore their surroundings with an array of molecular sensors. Contactin, a cell adhesion/recognition molecule discovered by Dr. Ranscht, is one of the molecular sensors exposed on the growth cone surface and is therefore a strong candidate to mediate growth cone recognition. To test the function of contactin in the establishment of axon connections in developing embryos, Dr. Ranscht's laboratory has recently generated contactin-deficient mice by manipulating the mouse genome. In support of the hypothesis that contactin is required for the formation of neuronal circuitry, the mutant mice show neurological defects: Their movements are severely uncoordinated and characteristic of those of patients diagnosed with ataxia. The mutant animals die shortly after birth. As the phenotype of contactin mutant mice is indicative of defects in neuronal circuits controlling motor behavior, Dr. Ranscht will produce a detail map of contactin distribution in brain areas controlling and modulating motor functions. Specifically, she will identify the neuron populations that use contactin for axonal pathfinding and clarify which of the identified contactin-binding proteins are distributed in the surroundings of contactin-positive neurons. To understand which molecular interactions are disrupted in the contactin mutant mice, the distribution and expression levels of contactin-binding proteins will also be examined in these mutants. Results from this project will contribute to understanding the role of contactin and its molecular interactions in neuronal circuits controlling motor functions.
