Mastermind-like 1 (MamL1) and mastermind-like 3 (MamL3) are essential for Notch signaling in vivo

Abstract

SUMMARYMastermind (Mam) is one of the elements of Notch signaling, a system that plays a pivotal role in metazoan development. Mam proteins form transcriptionally activating complexes with the intracellular domains of Notch, which are generated in response to the ligand-receptor interaction, and CSL DNA-binding proteins. In mammals, three structurally divergent Mam isoforms (MamL1, MamL2 and MamL3) have been identified. There have also been indications that Mam interacts functionally with various other transcription factors, including the p53 tumor suppressor, -catenin and NF-B. We have demonstrated previously that disruption of MamL1 causes partial deficiency of Notch signaling in vivo. However, MamL1-deficient mice did not recapitulate total loss of Notch signaling, suggesting that other members could compensate for the loss or that Notch signaling could proceed in the absence of Mam in certain contexts. Here, we report the generation of lines of mice null for MamL3. Although MamL3-null mice showed no apparent abnormalities, mice null for both MamL1 and MamL3 died during the early organogenic period with classic pan-Notch defects. Furthermore, expression of the lunatic fringe gene, which is strictly controlled by Notch signaling in the posterior presomitic mesoderm, was undetectable in this tissue of the double-null embryos. Neither of the single-null embryos exhibited any of these phenotypes. These various roles of the three Mam proteins could be due to their differential physical characteristics and/or their spatiotemporal distributions. These results indicate that engagement of Mam is essential for Notch signaling, and that the three Mam isoforms have distinct roles in vivo.

New insight into the SSC8 genetic determination of fatty acid composition in pigs

“…MAML3 is a member of the Mam gene family, which plays an essential role in the stabilization of Notch transcriptional activation complexes [33]. This Notch signaling pathway mediates short-range communication between cells, and it has recently been associated with the regulation of lipogenesis and gluconeogenesis in liver [34].…”

Olfactory Sensory Neurons Control Dendritic Complexity of Mitral Cells via Notch Signaling

“…ICR and C57BL/6J mice were purchased from CLEA, Japan. Generation of Maml1 -deficient mice has been previously described [20,42]. Mutant mice were backcrossed to C57BL/6J mice at least 10 times before use in the experiments.…”

Hematopoietic stem cell niche maintenance during homeostasis and regeneration

“…For example, inhibiting one protein required for the transcriptional activation of Notch signaling may result in the activation of compensatory pathways68. Resolution of the specificity of the cell types targeted for genetic deletion, the levels of Notch pathway inhibition and a study of the pathways under comparable conditions will be required to determine the extent to which Notch is necessary for HSC regulation.…”