Co-regulation of survival of motor neuron (SMN) protein and its interactorSIP1 during development and in spinal muscular atrophy

Spinal muscular atrophy (SMA) is a neuromuscular disease characterized by t he degeneration of motor neurons in the spinal cord. The disease is caused by mutations of the survival of motor neuron 1 gene (SMN1), resulting in a reduced production of functional SMN protein. A major question unanswered t hus far is why reduced amounts of ubiquitously expressed SMN protein specif ically cause the degeneration of motor neurons without affecting other soma tic cell types. In a first attempt to address this issue we have investigat ed the Smn interacting protein 1 (Sip1), with an emphasis on its developmen tal expression and subcellular distribution in spinal motor neurons in rela tion to Smn. By confocal immunofluorescence studies we provide evidence tha t a significant amount of Smn does not co-localize with Sip1 in neurites of motor neurons, indicating that Smn may exert motor neuron-specific functio ns that are not dependent on Sip1, Sip1 is highly expressed in the spinal c ord during early development and expression decreases in parallel with Smn during postnatal development. Strikingly, reduced production of Smn as obse rved in cell lines derived from SMA patients or in a mouse model for SMA co incides with a simultaneous reduction of Sip1. The finding that expression of Sip1 and Smn is tightly coregulated, together with the unique localizati on of Smn in neurites, may help in understanding the motor neuron-specific defects observed in SMA patients.