GENETIC CONTROL OF MONAMINERGIC AXON GROWTH

拟议的实验将调查遗传和环境

The proposed experiments will investigate the genetic and environmental mechanisms that affect normal axon growth in the developing mammalian nervous system. We will test 3 basic hypotheses: 1) Genes intrinsic to a neuron can control axon growth, 2) Genes regulate the responsiveness of neurons to extrinsic cues that modulate axon growth and 3) Gene defects that alter axon growth result in specific compensatory changes in normal parts of the system. A model system, based on a single locus gene mutation, will be used: The locus coeruleus (LC) noradrenergic neurons in the homozygous mutant mouse tottering (tg/tg) are a defined group of nerve cells whose exuberant axon growth in target areas is caused by a single locus gene mutation. We will transplant in oculo fetal LC neurons from tg/tg and normal (+/+) mice to determine whether the gene mutation altering axon growth affects directly an intrinsic developmental regulatory mechanisms in LC neurons. The intrinsic nature of the gene defect will also be assessed in tg/tg +/+ chimeras, using double labeling methods that combine in situ hybridization or enzyme histochemistry and immunocytochemistry to identify simultaneously genotype and phenotype. We will determine whether the single locus gene mutation has altered the ability of LC neurons to respond to environmental cues provided by targets or other fiber systems that normally contribute to the regulation of axon growth by the use of double (LC and target) and triple (LC, target and another fiber system) transplantation paradigms. The compensatory responses of LC afferents to the abnormal axon proliferation will be investigated using quantitative morphometric ultrastructural analysis. The relative contribution of the gene in influencing axongenesis will be observed by combining in a unique fashion different experiment systems. These studies may provide rational strategies for analyzing fiber growth abnormalities in development or following injury.