IMPAIRMENT OF MOTOR AXON DEVELOPMENT IN SPINAL MUSCULAR ATROPHY

Spinal muscular atrophy (SMA) is an inherited motor neuron disease caused by mutation of the survival of motor neuron 1(SMN1) gene and deficient expression of SMN protein. In humans, muscle weakness is traditionally thought to be determined by the magnitude of motor neuron degeneration. However, SMA mice show severe muscle weakness without substantial motor neuron loss suggesting that impaired function of motor neurons is the principal determinant of symptoms early in the disease course. Recent studies have also indicated that SMA may not be a motor neuron cell autonomous disease, but rather other cell types or tissues may play contributing role to SMA pathogenesis. In this study, we characterized ventral root (VR) motor axons at the light and electron microscopy level in SMA patient tissues collected at the time of autopsy and in SMA mice. Our results reveal a significant reduction of large myelinated axons, but a surprising, large increase of small unmyelinated axons in both human and mouse SMA VRs, suggesting an early arrest of axonal development. As axonal radial growth is dependent on interactions between axons and Schwann cells, we hypothesized that SMN-deficient Schwann cells contribute to impaired motor axonal growth and to muscle weakness in SMA. To explore the relative contribution of SMN-deficient motor neurons and Schwann cells to the axonal pathology in SMA, we utilized conditional SMA mouse lines with full-length SMN expression selectively increased in motor neurons ( ChATCre+ SMA), Schwann cells (DhhCre+ SMA), or both (ChATCre+DhhCre+ SMA). Behavioral data did not show any significant improvements in the motor behavior, survival, or body weight of the DhhCre+ SMA mice compared with the DhhCre- SMA mice. In contrast, ChATCre+ SMA showed a significant improvement in motor function, survival, and body weight, along with improved number of mature motor axons. ChATCre+DhhCre+ SMA mice did not show additional synergistic effect beyond what is observed in the ChATCre+ SMA mice. These findings suggest that motor axon development is impaired in SMA mice largely due to deficiency of SMN in motor neurons. SMN-deficient Schwann cells do not appear to contribute to impairments of motor axon radial growth in SMA