This proposal outlines a genetic test of the hypothesis that signaling by the Fas receptor contributes to naturally occurring and pathologic cell death of motor neurons. Previous research from the Henderson laboratory has identified an autocrine signaling mechanism for motor neuron death following growth factor withdrawal that requires the induction of Fas ligand and activation of the Fas receptor. Subsequent characterization of this process revealed a motor neuron specific signaling pathway for the Fas receptor that requires nNOS and is highly sensitized in transgenic mouse models of ALS in which mutant SOD1 is overexpressed.
Our specific aims are to (1) Characterize the role of FasL during motor neuron development, (2) Generate a conditional null for Fas with a linked reporter, and (3) Genetically test the contribution of Fas signaling to mutant SOD1 linked motor neuron cell death in a mouse model of ALS. Using a battery of established criteria for analyzing motor function, animal behavior, and tissue histology, we will examine the consequences of Fas disruption on normal developmental cell death and the progression of pathologic cell death in the SOD mutant mice, and will define the expression of Fas during both processes. ? ?
