Sprouting as a compensatory mechanism in Smn-deficient mice

Centre for Integrative Physiology, University of Edinburgh,  and Euan Macdonald Centre, University of Edinburgh

Spinal muscular atrophy (SMA) is a neuromuscular disorder, caused by homozygous loss or mutation of the survival motor neuron 1 (SMN1) gene. This leads to a reduction in its protein product, Smn. As a result, SMA is characterised by the degeneration of motor neurons and progressive atrophy of skeletal muscles. It is the most common genetic cause of infant mortality. Interestingly, some mouse models with reduced Smn protein are asymptomatic. Mice which have only 15% of regular Smn levels (Smn2B/-) present a phenotype reflective of SMA. However, mice with 50% (Smn+/-) and those with 30% Smn levels (Smn2B/2B) both appear asymptomatic and have a normal lifespan. This suggests there is a threshold to which Smn levels must drop before presenting a phenotype. Is this lack of phenotype in these mouse models therefore due to sufficient levels of Smn protein (i.e. above the critical threshold), meaning that motor neurons are capable of survival – or could other methods be underlying this phenomenon? Previous studies have suggested that compensatory sprouting mechanisms could be masking the disease phenotype. To investigate this, we looked at factors which initiate sprouting (CNTF and IGF2) and analysed the morphological changes seen at the level of the neuromuscular junction in these mice. Morphological analyses suggest that sprouting could play a role as a phenotypic modifier in younger mouse models below the apparent threshold level of Smn. Sprouting does not seem morphologically apparent in Smn+/- or Smn2B/2B mice. Molecular analyses show no significant upregulation of CNTF and IGF2 in these mice either, however future investigations could reveal the involvement of other sprouting factors.

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