title: Restoration of SMN to Emx-1 expressing cortical neurons is not sufficient to provide benefit to a severe mouse model of Spinal Muscular Atrophy.
abstract: Spinal Muscular Atrophy (SMA), an autosomal recessive neuromuscular disorder, is a leading genetic cause of infant mortality. SMA is caused by the homozygous loss of Survival Motor Neuron-1 (SMN1). However, low, but essential, levels of SMN protein are produced by a nearly identical copy gene called SMN2. Detailed analysis of neuromuscular junctions in SMA mice has revealed a selective vulnerability in a subset of muscle targets, suggesting that while SMN is reduced uniformly, the functional deficits manifest sporadically. Additionally, in severe SMA models, it is becoming increasing apparent that SMA is not restricted solely to motor neurons. Rather, additional tissues including the heart, vasculature, and the pancreas contribute to the complete SMA-associated pathology. Recently, transgenic models have been utilized to examine the tissue-specific requirements of SMN, including selective depletion and restoration of SMN in motor neurons. To determine whether the cortical neuronal populations expressing the Emx-1 promoter are involved in SMA pathology, we generated a novel SMA mouse model in which SMN expression was specifically induced in Emx-1 expressing cortical neurons utilizing an Emx-1-Cre transgene. While SMN expression was robust in the central nervous system as expected, SMA mice did not live longer. Weight and time-to-right motor function were not significantly improved.
authors.affiliation: Department of Veterinary Pathobiology, Life Sciences Center, University of Missouri, Room 471G, Columbia, MO, 65211, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Taylor
authors.forename: Jacqueline J
authors.initials: JJ
authors.lastname: Glascock
authors.forename: Ferrill F
authors.initials: FF
authors.lastname: Rose
authors.forename: Cathleen
authors.initials: C
authors.lastname: Lutz
authors.forename: Christian L
authors.initials: CL
authors.lastname: Lorson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D005838:Genotype; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism*; D019076:Transgenes / Q000235:genetics; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D018398:Homeodomain Proteins; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C526477:SMN2 protein, human