Mastermind critically regulates Notch-mediated lymphoid cell fate decisions

Abstract

IntroductionNotch signaling plays a central role in multiple developmental processes. During blood and lymphoid development, Notch proteins influence several hematopoietic lineages. At the T-cell/B-cell branchpoint, Notch promotes T-cell at the expense of B-cell differentiation. 1,2 More recent data implicate Notch1 in the early generation of the hematopoietic stem cell (HSC) pool during embryogenesis 3 and Notch2 in marginal zone B-cell (MZB) development. [4][5][6] Notch family members also have been postulated to play a role in HSC self-renewal and homeostasis. 7,8 Other putative roles of Notch in the CD4/CD8 lineage choice, in ␣␤ versus ␥␦ T-cell differentiation and in the function of peripheral T cells are more controversial (reviewed in Radtke et al 9 and Maillard et al 10 ).Part of the lingering uncertainty over the role of Notch signals in hematopoiesis is related to the existence of multiple receptors and ligands with complex patterns of expression. Notch proteins are transmembrane receptors interacting with ligands of the Jagged and Delta-like families. Mammals have 4 different Notch receptors (Notch1-4) with a similar overall structure (reviewed in Radtke et al 9 and Maillard et al 10 ). Notch-mediated transcriptional activation involves proteolytic cleavage and physical translocation of the Notch intracellular domain (ICN) into the nucleus. Once in the nucleus, ICN binds to CSL (CBF1/RBP-Jk, Suppressor of Hairless, Lag-1), a transcription factor that mediates most of the wellcharacterized Notch functions. ICN binding has 2 consequences. First, it displaces co-repressors from CSL, resulting in derepression of promoters with CSL binding sites. 11 Secondly, ICN recruits Mastermind-like (MAML) proteins, 12 which appear to function as a scaffold for the formation of a large multiprotein transcriptional activation complex. 13 Three MAML family members (MAML1-3) have been identified in mammals. 14,15 MAMLs are nuclear proteins with short basic N-terminal sequences that bind the ankyrin repeat domain of ICN, and C-termini that recruit p300 and other transcriptional activators. In vitro experiments suggest that MAMLs are critical for Notch-mediated stimulation of CSL-dependent transcription 12,[14][15][16] and have shown that truncated MAML mutants consisting of only the N-terminal ICN-binding domain have potent dominant negative effects, presumably due to their inability to recruit other components of the Notch transcriptional activation complex. 16,17 The minimal region of MAML1 required for ICN binding, a basic region comprising amino acids 13 to 74, is sufficient to form a stable ternary complex with purified CSL and ICN (Nam et al 18 ) and when overexpressed in transfection assays, generates a profound block in Notch1-mediated transcriptional activation. 17 Furthermore, this minimal MAML1 13-74 region causes growth arrest and apoptosis of multiple T-ALL cell lines bearing constitutively active Notch1 alleles. 17 Although these data suggest that MAML proteins may be critical components of the Notch signali...

Mastermind-like transcriptional co-activators: emerging roles in regulating cross talk among multiple signaling pathways

“…Importantly, these effects are consistent with phenotypes caused by the inactivation of canonical Notch signaling in these compartments, because loss of the transcription factor CSL blocks both T-cell development and MZB cell generation Tanigaki et al, 2002). Not unexpectedly, then, the expression of DNMAML1 in bone marrow cells abrogated canonical Notch signaling, inhibiting both T-cell development and MZB cell generation (Maillard et al, 2004). Taken together, these data revealed that the MAML genes collectively are essential in mediating physiological Notch functions.…”

Characterization of CSL (CBF-1, Su(H), Lag-1) Mutants Reveals Differences in Signaling Mediated by Notch1 and Notch2

“…4, G and H). Although DNMAM has been shown to be an effective inhibitor of signaling mediated by Notch2 in previous studies (35), these data may suggest that NICD2 is functioning independently of MAM in this specific cellular context. Certainly, additional studies are needed to validate this hypothesis; however, the molecular basis for the lack of NICD2 inhibition by DNMAM was not pursued further in this study.…”

The Notch signaling pathway: Transcriptional regulation at Notch target genes

“…Mammalian MAML was shown to stabilize the RBP/NICD bound to DNA during activation of target genes [102]. In vivo, the importance of MAML has been impressively demonstrated with dominant-negative MAML, which completely blocks all Notch-mediated transcriptional activation [106]. This tool has been exploited to study the physiological role of "canonical" (RBP-J dependent) Notch signaling in detail, reviewed in [107].…”