Mouse Models For Spinal Muscular Atrophy

A review of: Jablonka S, Schrank B, Kralewski M, Rossoll W, Sendtner M 2000 Reduced survival motor neuron (Smn) gene dose in mice leads to motor neuron degeneration: an animal model for spinal muscular atrophy type III. Hum Mol Genet 9:341–346. Hsieh-Li HM, Chang JG, Jong YJ, Wu MH, Wang NM, Tsai CH, Li H 2000 A mouse model for spinal muscular atrophy. Nat Genet 24:66–70. Monani UR, Sendtner M, Coovert DD, Parsons DW, Andreassi C, Le TT, Jablonka S, Schrank B, Rossol W, Prior TW, Morris GE, Burghes AH 2000 The human centromeric survival motor neuron gene (SMN2) rescues embryonic lethality in Smn(−/−) mice and results in a mouse with spinal muscular atrophy. Hum Mol Genet 9:333–339.

Despite some initial confusion, it is clear that deletions of the SMN1 (survival motor neuron) gene are necessary and sufficient for almost all cases of the autosomal recessive neurodegenerative disorder, spinal muscular atrophy (SMA). Now, in a welcome advance, three recent papers describe mice genetically engineered to have low levels of SMN protein, all with the SMA hallmark motor neuron loss and, in two cases, phenotypic features of SMA.

The SMN protein is essential for RNA splicesomal biogenesis and, not surprisingly, life; ablation of the mouse SMN gene results in very early fetal wastage. However, human infants with SMN1 gene deletions survive, albeit with SMA. This difference is due to a second copy of SMN in humans, SMN2, an aberrantly spliced gene which generates only enough full length SMN transcript to ensure survival but not, in the longer term, of all the motor neurons. The number of SMN2 copies is polymorphic: in general, the more copies of SMN2 in a child with SMA, the milder the disease.

Analysis of mice heterozygous for the SMN deletion (SMN +/− mice) has revealed that the halving of SMN protein concentrations leads to loss of half the motor neurons in spinal cord and a quarter of those in cranial nerve VII (facial) by 12 months (¹). These mice do not demonstrate any weakness in contrast to SMN (−/−) mice which were rescued with human SMN2 transgenes, in which phenotype severity and the motor neuron counts vary inversely with SMN2 copy number (^{2, 3}). Mice with one SMN2 copy die throughout the first postnatal week and, prior to dying, show a precipitous drop in motor neuron count. In contrast, a milder SMA 2 picture is seen with two to three copies (¹) while those with an estimated eight copies of SMN2 are normal (²).

Interestingly, the motor neuron counts at birth for even the most SMN deficient mice are normal; neuronal drop-out occurs exclusively postnatally, not overlapping with the natural apoptosis of motor neurons observed from embryonic day 10.5 to day 16. Although postnatal motor neuron attrition is desirable when thinking of therapeutic approaches, it is worth noting that many of the single SMN2 copy SMN (−/−) mice die prior to neuronal loss, suggesting a dysfunction of these cells and/or other cellular types preceding actual cell death.

We now await mice with developmentally and spatially defined SMN deficiency to establish 1) whether the cytopathic effect conferred by SMN depletion is restricted to motor neurons, if this is sufficient for SMA or if an unappreciated non-neuronal cellular dysfunction or death is involved, and 2) the developmental period over which SMN deficiency confers pathogenicity, postnatally and/or prenatally.

Still unresolved is why SMN deficiency kills motor neurons: is it a loss of SMN mediated snRNP complex regeneration affecting a subset of all motor neuron transcripts or are other unrecognized SMN role(s) responsible? The analysis of mice deficient in proteins such as SMN interacting splicesomal situated SIP1 protein will aid in clarifying this issue.

Ultimately, however, the mouse work neatly confirms the model predicted from the human data: SMN derived from SMN2 modulates SMA severity. The same animal models are now a valuable resource in the next logical step in the search for therapies for this fatal illness—identifying and testing agents that enhance the SMN production originating from SMN2.