Cloning and functional characterization of the murine mastermind-like 1 (Maml1) gene.

The Notch signaling pathway controls cell fate decisions and plays a critical role in normal development and diseases. The human mastermind-like (MAML) family members (MAML1, 2 and 3) encode critical transcriptional co-activators for Notch receptors. In this study, we cloned a murine cDNA that is highly homologous to the human MAML1 gene, Maml1. Mouse Maml1 encodes a nuclear protein, binds to the ankyrin repeat domain of Notch receptors, forms a ternary complex with the intracellular domain of Notch (ICN) and the DNA binding protein CSL, and enhances Notch-induced transcription of the target gene, HES-1. Therefore, Maml1 is the murine homologue for human MAML1 and functions as a transcriptional co-activator for Notch signaling. We also characterized the organization of the mouse Maml1 gene: It spans at least 35 kilobases (kb) on chromosome 11 and contains five exons and four introns. Analysis of the 5' flanking region revealed that the promoter is TATA-less, and contains consensus binding sites for transcription factors such as Sp1, glucocorticoid receptor (GR), activating transcription factor (ATF) and cAMP response element-binding protein (CREB). Moreover, we examined Maml1 expression during early mouse development and found that Maml1 gene is expressed widely but selectively in several tissues. There seems to be close correlation of the spatial and temporal expression among Maml1, Notch1 and Hes1 in the central nervous system (CNS) during early development, implicating a role for the Maml1 gene in neurogenesis.