Chondrolectin affects cell survival and neuronal outgrowth in in vitro and in vivo models of spinal muscular atrophy.
Spinal muscular atrophy (SMA) is characterized by the selective loss of spinal motor neurons owing to reduced levels of survival motor neuron (Smn) protein. In addition to its well-established role in assembling constituents of the spliceosome, diverse cellular functions have been proposed for Smn, but the reason why low levels of this widely expressed protein result in selective motor neuron pathology is still debated. In longitudinal studies of exon-level changes in SMA mouse model tissues, designed to determine the contribution of splicing dysfunction to the disease, we have previously shown that a generalized defect in splicing is unlikely to play a causative role in SMA. Nevertheless, we identified a small subset of genes that were alternatively spliced in the spinal cord compared with control mice before symptom onset, indicating a possible mechanistic role in disease. Here, we have performed functional studies of one of these genes, chondrolectin (Chodl), known to be highly expressed in motor neurons and important for correct motor axon outgrowth in zebrafish. Using in vitro and in vivo models of SMA, we demonstrate altered expression of Chodl in SMA mouse spinal motor neurons, show that Chodl has distinct effects on cell survival and neurite outgrowth and that increasing the expression of chodl can rescue motor neuron outgrowth defects in Smn-depleted zebrafish. Our findings thus link the dysregulation of Chodl to the pathophysiology of motor neuron degeneration in SMA.
Department of Physiology, Anatomy and Genetics, MRC Functional Genomics Unit, University of Oxford, South Parks Road, Oxford OX1 3PT, UK.
James N
JN
Sleigh
Antón
A
Barreiro-Iglesias
Peter L
PL
Oliver
Angeliki
A
Biba
Thomas
T
Becker
Kay E
KE
Davies
Catherina G
CG
Becker
Kevin
K
Talbot
D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D006801:Humans; D037181:Lectins, C-Type / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism*; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D016501:Neurites / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish
D037181:Lectins, C-Type; D055533:Survival of Motor Neuron 1 Protein; C474775:chondrolectin, mouse; C526474:smn1 protein, zebrafish