{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMastermind‐like (MAML) proteins serve as essential transcriptional co‐activators in the canonical Notch signaling pathway. They bind directly to the intracellular domains of Notch receptors and the CSL family of DNA‐binding proteins to form ternary complexes that activate numerous target genes. Studies in mice have demonstrated that MAML proteins, including MAML1 and its isoforms, are required for proper cell fate decisions in multiple tissues. For example, cloning and characterization of murine Maml1 revealed its nuclear localization, its binding to Notch receptors, and its enhancement of Notch‐responsive gene transcription in early development."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in Notch signaling, the MAML family has been found to integrate and modulate multiple additional pathways that impact diverse cellular processes. In the hematopoietic compartment, for instance, interference with MAML function disrupts T‐cell commitment and marginal zone B cell development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " In the muscle, loss of Maml1 results in profound myogenic defects and severe muscular dystrophy, a phenotype linked to its role as a co‐activator for MEF2C."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, MAML1 modulates non‐Notch pathways: it participates in the destabilization mediated by Mesp2 during somite rostro‐caudal patterning"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": ", governs NF‑κB responses to TNFα"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and functions as a co‐activator of Runx2 in bone and chondrocyte development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAdditional studies have expanded the spectrum of MAML1’s roles. In the central nervous system, downregulation or dominant negative manipulation of MAML alters cortical neurogenesis, induces premature neuronal production, and disrupts proper neuronal migration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Similarly, MAML1 influences the dendritic architecture of mitral cells in the olfactory bulb"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "and modulates cerebellar granule cell progenitor proliferation via cooperation with Sonic hedgehog signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " In the context of glial development, inhibition of Notch signaling via dominant negative MAML accelerates oligodendrocyte differentiation and enhances remyelination."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Furthermore, in ocular surface epithelia, MAML‐dependent Notch signaling is critical for goblet cell differentiation and mucin synthesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": ", while modulation of MAML1 by specific microRNAs impacts cardiomyocyte survival and reduces ischemia–reperfusion injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings underscore the multifaceted function of MAML proteins as central co‐activators that regulate Notch‐dependent transcription and mediate extensive cross‐talk with other key signaling pathways. Their critical involvement in lymphopoiesis, myogenesis, osteogenesis, neurogenesis, remyelination, and even immune modulation positions them as promising therapeutic targets in developmental disorders, cancer, demyelinating diseases, and cardiac injury."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "7"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "6"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "4"}, {"type": "fg_f", "ref": "14"}, {"type": "fg_f", "ref": "5"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "15"}, {"type": "fg_f", "ref": "13"}, {"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Lizi Wu, Karla Kobayashi, Tao Sun, et al. 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