Smad Interacting Protein-1 is Essential for Oligodendrocyte Differentiation

Abstract Precursor/stem cell substitutive therapy to promote remyelination is an ideal strategy for central nervous system demyelinating diseases such as spinal cord injury (SCI). However, the microenvironment of the injured area is not conducive to the survival, differentiation, and functions of the transplanted cells. Identifying and regulating the key inhibitory factors might be an important target for the treatment of demyelinating diseases. Smad interacting protein-1 (Sip1) is a transcription factor that binds to phosphorylated R-Smad in the nucleus, which promotes remyelination by inducing the differentiation of oligodendrocytes. In this study, we show that the expression of Sip1 is up-regulated and peaks by 1 day and then returns to normal levels 7 days after SCI. Most Sip1 positive cells were oligodendrocytes. In vitro, Sip1 was weakly expressed in the cytoplasm of oligodendrocyte progenitor cells (OPCs), significantly up-regulated in immature oligodendrocytes, and showed significant nuclear transposition. In contrast, Sip1 expression levels in mature oligodendrocytes decreased to levels similar to those in OPCs. The RNA interference of Sip1 in OPCs reduced the level of myelin basic protein (a mature oligodendrocyte marker protein, MBP) and pERK1/2 (a key molecule of the ERK/MAPK pathway) in oligodendrocytes. These findings suggest that Sip1 is essential for oligodendrocyte differentiation and might affect the ERK/MAPK signal pathway. The results provide a theoretical basis for the treatment of demyelinating lesions such as spinal cord injury by regulating Sip1 expression in oligodendrocytes.