Comment on Maillard et al, page 1696
Retroviral transduction of hematopoietic stem cells with a dominant interfering form of Mastermind has revealed an in vivo role in vertebrates for the Mastermind-like family of Notch regulators during lymphocyte development.
The Notch mutation in Drosophila was originally described by Morgan in 1917. There are 4 distinct vertebrate Notch genes that are expressed at different levels in distinct tissues and cell types. Notch proteins are cell surface receptors that bind to spe cific membrane-associated ligands. Ligation of Notch results in the proteolytic release of the intracellular domain of this receptor. This intracellular fragment of Notch translocates to the nucleus, where it forms a ternary complex with a DNA-binding protein called recombination binding protein J κ/C-promoter binding factor 1 (RBP-Jκ/CBF1; the vertebrate ortholog of Drosophila Suppressor of Hairless) and a protein called Mastermind. Mastermind was identified in Drosophila as a positive regulator of Notch signaling. Biochemical studies have established that Mastermind links intracellular Notch and RBP-Jκ to coactivator complexes and thus facilitates the transcription of Notch targets. The Deltex gene has been viewed as both a positive and negative regulator of Notch in different cell types and organisms. Its biochemical role in Notch signaling is poorly understood.
In hematopoietic cells in vertebrates, the Notch pathway appears to serve as a means to ensure that selected lineage commitment events proceed in a binary manner. In central lymphoid organs such as the bone marrow and thymus, the decision to become a T cell rather than a B cell requires signaling via Notch1. Two distinct B-lymphocyte lineages develop in the spleen. Mature follicular B lymphocytes are recirculating cells that mature in response to antigen receptor-derived signals. A second lineage of B cells, known as marginal zone (MZ) B cells, resides in close proximity to specialized macrophages that surround an anastomosing arteriolar sinus known as the marginal sinus. MZ B cells are extremely long-lived lymphocytes that respond rapidly to blood-borne pathogens and can participate in both T-independent as well as T-dependent immune responses. These B cells do not develop from clones that receive relatively strong antigen receptor-mediated signals1 but require signals from Notch2 and its ligand delta-like-1,2-4 as revealed by conditional gene targeting studies. Notch2 apparently intercedes during B-cell development to ensure the generation of a second B-cell lineage in the spleen.
Maillard and colleagues report the transduction of lymphoid progenitors with a truncated N-terminal form of Mastermind-like-1 (MAML1) that can associate with intracellular Notch but lacks the C-terminal transcriptional activation domain of the full-length protein. This dominant interfering MAML1 blocks Notch1-dependent T-lineage commitment and Notch2-dependent MZ B-cell development, thus demonstrating an in vivo function for Mastermind in vertebrates. Expression in lymphoid progenitors of wild-type Deltex1 blocks commitment to the T-lineage but does not block MZ B-cell development. It is possible that Deltex 1 might actually function as a negative regulator of Notch1 in the bone marrow and a positive regulator of Notch2 signaling in the spleen. There are 3 Mastermind-like genes in vertebrates, and conditional inactivation of MAML1, MAML2, and MAML3 may be required to elucidate which Mastermind ortholog(s) regulates Notch transcription during lymphocyte development in the bone marrow and the spleen.
