Role of RAGE signalling in peripheral nerve regeneration and in mediating the neurotrophic effects of the HNK-1 carbohydrate

点击翻译按钮获取中文摘要

Although regeneration in the peripheral nervous system is not generally inhibited, as it is in the central nervous system of adult mammals, nerve repair in humans are often not adequate due to the problem of incomplete or faulty targeting. Preferential motor reinnervation of the femoral nerve has been paradigmatic in our studies on the accuracy of motoneuron pathfinding and uncovering the molecular determinants of this preferential regrowth of motor axons into the correct branch of the femoral nerve at the choice point where the femoral nerve bifurcates. We propose to investigate preferential motor reinnervation by perturbation experiments in adult mice by testing the outcome of application of the receptor for advanced glycation end products (RAGE), which is a receptor for amphoterin, which in turn binds to the HNK-1 carbohydrate in adult mice. This carbohydrate and its glycomimetic were shown by us to be instrumental in enhancing preferential motor reinnervation in the mouse. We will also test regeneration in adult mice that are genetically deficient in RAGE. Regeneration will also be tested in transgenic mice that express dominant-negative RAGE under the control of the Thy-1 promoter. Since the brain-derived neurotrophic factor and its cognate receptor are involved in regulation of HNK-1 carbohydrate expression, we will try to circumvent deficiency in HNK-1 upregulation after femoral nerve transection by applying the HNK-1 glycomimetic to the injured femoral nerve of these mutant mice. The combined experiments should yield insights into the molecular mechanisms of preferential motor reinnervation with the hope to translate this knowledge into a therapeutically valuable approach in primates.