Understanding mechanisms that lead to selective motor neuron degeneration requires visualization and cellular identification of vulnerable neurons. Here we report generation and characterization of UCHL1-eGFP and hSOD1G93A-UeGFP mice, novel reporter lines for cortical and spinal motor neurons. Corticospinal motor neurons (CSMN) and asubset of spinalmotorneurons(SMN)are genetically labeled inUCHL1-eGFP mice, which express eGFP under the UCHL1 promoter. eGFP expression is stable and continues through P800 in vivo. Retrograde labeling, molecular marker expression, electrophysiological analysis, and cortical circuit mapping confirmed CSMN identity of eGFPα neurons in the motor cortex. Anatomy, molecular marker expression, and electrophysiological analysis revealed that the eGFP expression is restricted to a subset of small-size SMN that are slow-twitch α and γ motor neurons. Crossbreeding of UCHL1-eGFP and hSOD1G93A lines generated hSOD1G93A-UeGFPmice, which displayed the disease phenotype observed in ahSOD1G93A mouse model of ALS.eGFP+SMN showed resistance to degeneration inhSOD1G93A-UeGFPmice, andtheir slow-twitchαandγ motorneuron identitywasconfirmed. In contrast, eGFP+ neurons in the motor cortex of hSOD1G93A-UeGFP mice recapitulated previously reported progressive CSMN loss and apical dendrite degeneration. Our findings using these two novel reporter lines revealed accumulation of autophagosomes along the apical dendrites of vulnerable CSMN at P60, early symptomatic stage, suggesting autophagy as a potential intrinsic mechanism for CSMN apical dendrite degeneration.
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