"Our study uncovered an exciting and essential regulatory role for Maml1 in muscle development," says Wu.
Dr. Wu and colleagues generated MAML1-deficient mice, which displayed severe muscular dystrophy. The researchers showed that the modulation of MAML1 expression levels in cell culture experiments directly impacts the ability of the muscle gene transcription factor, MEF2C, to induce myogenesis: Increased MAML1 expression leads to enhanced myotube formation and increased expression of muscle-specific target genes, while reduced MAML1 expression impairs muscle cell differentiation. It appears that MEF2C and MAML1 work together in a complex to "turn on" several other genes that are required for muscle development and function.
However, MAML1's pro-myogenic effects are only observed when Notch receptors are inactive. The authors believe that MAML1 serves as a co-activator for MEF2C, but upon Notch activation, MAML1 is recruited away from MEF2C by Notch, thereby down-regulating muscle-specific target genes and up-regulating Notch target genes. "Our study uncovered an exciting and essential regulatory role for the Maml1gene in myogenesis and suggested that a mis-regulation of Maml1 gene function might contribute to the pathology of muscle myopathies," explains Dr. Wu.
There are two other genes that are similar to MAML1 in humans: MAML2 and MAML3, and Wu and colleagues are working to determine their functions as well.
Journal
Genes & Development