{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNODAL is a fundamental morphogen that governs early embryonic development by maintaining pluripotency and directing germ layer patterning. In human embryonic stem cells, NODAL signaling—operating in concert with Activin and FGF pathways—sustains the undifferentiated state by preventing default neuroectoderm differentiation, while also promoting mesendoderm formation through regulation of key pluripotency factors such as Nanog. Moreover, even under mechanical strain, NODAL (as part of the TGFβ/Activin/NODAL network) contributes to the robust maintenance of stem cell identity and orchestrates a timely transition toward differentiation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nDuring early embryogenesis, NODAL also plays an essential role in the establishment of axial structures and laterality. In the mouse embryo, for example, NODAL is expressed from the primitive streak through the organizer (node) to induce mesoderm formation and determine left–right asymmetry. In addition, alterations in NODAL expression—whether through genetic mutations or regulation by microRNAs—have been linked to congenital malformations such as heterotaxy, cardiovascular defects, and preeclampsia, highlighting its critical role in orchestrating cell-fate decisions during tissue and organ formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cancers, aberrant reactivation of NODAL is associated with enhanced tumor aggressiveness and cellular plasticity. Reactivated NODAL signaling—often mediated via co-receptors such as Cripto—has been shown to promote invasive behavior, facilitate cell cycle deregulation (for example, by upregulating cyclin G2 via FoxO3a), and sustain an undifferentiated, stem cell–like phenotype in tumors of the brain, ovary, breast, and prostate. Furthermore, the ability of NODAL to engage in synthetic reaction–diffusion networks with its antagonist Lefty demonstrates its potent capacity to self‐organize spatial information, which may further influence both developmental patterning and tumor cell behavior. Recent findings even point to roles for nodal‐related long noncoding RNAs in modulating cardiomyocyte cell cycle re–entry, expanding the spectrum of NODAL’s regulatory functions in both development and disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "X Zhou, H Sasaki, L Lowe, et al. 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