MAML1 in the Crosstalk between Notch and Hedgehog Pathways in Differentiation and Disease

Background: Several pathways interact in the regulation of cellular processes, such as differentiation, survival and proliferation, in each tissue of an organism. Regarding the differentiation of T lymphocytes, Notch and Hedgehog (Hh) pathways play a fundamental role. The molecular mechanisms that control these two pathways must be finely regulated, since it is known that their alterations can lead to the onset of several diseases. It has been shown that Notch and Hh are turned on and off in different stages of T cell development and these observations suggest that Notch and Hh signaling could be mutually exclusive. In this work, we suggest that MAML1, a known co-activator of Notch-driven transcriptional complex, could play a role in regulating the crosstalk between these two pathways. Methods: Murine models and MEFs (mouse embryonic fibroblasts), in vitro cell line treatments, luciferase assays, in vitro expression of recombinant proteins, immunoprecipitation, analysis of gene expression with qPCR, and chromatin immunoprecipitation (ChIP) were utilized in this study. Results: We show that MAML1 acts as co-activator in the Hh pathway, empowering the activity of the transcription factor Gli1. Furthermore, our studies suggest a possible role of MAML1 in sustaining the activity of Hh pathway, probably by interfering with the degradation processes affecting Gli1. Conclusions: Our preliminary observations suggest that MAML1 might be the new co-activator of the transcription factor Gli1, in a Notchindependent manner, and could play a pivotal role in influencing the delicate balance between these two pathways.