{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FAT4, an atypical cadherin, has emerged as a multifunctional molecule that plays critical roles in both normal development and tumor suppression. In developmental systems, FAT4 is a key regulator of planar cell polarity (PCP) and tissue morphogenesis. Its activity is required for the proper orientation of cell divisions and the elongation of tubular structures during kidney development, as loss of FAT4 disrupts these processes and leads to cystic disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In the developing nervous system, mutations in FAT4—as observed in combination with its ligand DCHS1—cause periventricular neuronal heterotopia by impairing the transition from progenitor expansion to differentiation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Similarly, FAT4 expression in the renal stroma contributes to epithelial progenitor differentiation by mediating stromal signals that balance nephron progenitor renewal and differentiation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "and restricts progenitor self‐renewal in the developing kidney."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In the heart, FAT4 modulates Hippo pathway signaling by sequestering the coactivator Amotl1, thereby limiting cardiomyocyte proliferation and controlling myocardial growth"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": ", while in the cerebral cortex, FAT4 together with Dachsous1 helps to organize the apical plasma membrane in neural progenitors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to its developmental functions, FAT4 exhibits tumor‐suppressor activity in several human malignancies. Somatic mutations and genomic deletions affecting FAT4 have been identified in gastric cancers, where inactivation of FAT4 promotes tumorigenesis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": ", as well as in breast tumors, where loss of FAT4 expression through promoter methylation is linked to malignant transformation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Recurrent FAT4 mutations have also been reported in acinar cell carcinoma of the pancreas"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", in chronic myelomonocytic leukemia"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": ", and in extranodal natural killer/T cell lymphoma"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", underscoring its broad tumor‐suppressive roles.\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, germline mutations in FAT4 have been implicated in rare developmental syndromes such as Hennekam syndrome, linking FAT4 dysfunction to lymphatic dysplasia and overlapping clinical features with Van Maldergem syndrome."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Collectively, these findings highlight that FAT4 integrates extracellular adhesion signals with intracellular pathways—including components of the Hippo cascade—to direct proper tissue architecture during organogenesis and to restrain uncontrolled cell proliferation in cancer.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sakura Saburi, Ian Hester, Evelyne Fischer, et al. 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