title: eGFP expression under UCHL1 promoter genetically labels corticospinal motor neurons and a subpopulation of degeneration-resistant spinal motor neurons in an ALS mouse model.
abstract: 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 hSOD1(G93A)-UeGFP mice, novel reporter lines for cortical and spinal motor neurons. Corticospinal motor neurons (CSMN) and a subset of spinal motor neurons (SMN) are genetically labeled in UCHL1-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 eGFP(+) 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 hSOD1(G93A) lines generated hSOD1(G93A)-UeGFP mice, which displayed the disease phenotype observed in a hSOD1(G93A) mouse model of ALS. eGFP(+) SMN showed resistance to degeneration in hSOD1(G93A)-UeGFP mice, and their slow-twitch α and γ motor neuron identity was confirmed. In contrast, eGFP(+) neurons in the motor cortex of hSOD1(G93A)-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.
authors: Davee Department of Neurology and Clinical Neurological Sciences, Northwestern University, Feinberg School of Medicine, Chicago, Illinois 60611, USA.
authors: Marina V
authors: MV
authors: Yasvoina
authors: Baris
authors: B
authors: Genç
authors: Javier H
authors: JH
authors: Jara
authors: Patrick L
authors: PL
authors: Sheets
authors: Katharina A
authors: KA
authors: Quinlan
authors: Ana
authors: A
authors: Milosevic
authors: Gordon M G
authors: GM
authors: Shepherd
authors: C J
authors: CJ
authors: Heckman
authors: P Hande
authors: PH
authors: Özdinler
mesh_terms: D000367:Age Factors; D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics; D066298:In Vitro Techniques; D007834:Lasers; D008297:Male; D008564:Membrane Potentials / Q000235:genetics / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009434:Neural Pathways / Q000473:pathology; D018408:Patch-Clamp Techniques; D010775:Photic Stimulation; D013116:Spinal Cord / Q000473:pathology*; D013482:Superoxide Dismutase / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D043222:Ubiquitin Thiolesterase
chemical_list: D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D014157:Transcription Factors; C482860:UCHL1 protein, human; C084059:Hb9 protein, mouse; D049452:Green Fluorescent Proteins; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D043222:Ubiquitin Thiolesterase
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