{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTMEM131L is a transmembrane protein that plays a critical role in T cell development by regulating key signaling pathways. In human hematopoietic progenitor cells, TMEM131L normally acts to restrict thymocyte proliferation during thymopoiesis. Loss of TMEM131L function leads to thymocyte hyperproliferation, developmental abnormalities, and an abnormal activation of the canonical Wnt/β‐catenin pathway. Mechanistically, its membrane-associated form promotes lysosome‐dependent degradation of the active, phosphorylated form of the LRP6 co‐receptor, thereby limiting Wnt signaling. This inhibitory effect appears to depend on a conserved extracellular domain, rather than the cytoplasmic domain, suggesting a stage-specific localization on the thymocyte surface is crucial for its regulatory role."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a complementary study using a heterospecific Drosophila transgenic model and human cells, TMEM131L was further shown to impact the Notch signaling pathway by decreasing the production of key ligands such as Wingless. Overexpression of TMEM131L in human CD34⁺ progenitor cells rendered them less responsive to Notch1 engagement and impaired their commitment to the T cell lineage. These findings underscore that TMEM131L not only inhibits canonical Wnt/β-catenin signaling through targeted degradation of phosphorylated LRP6 but also acts as an evolutionarily conserved modulator of Notch signaling, thereby integrating multiple regulatory inputs during T cell development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these studies reveal that TMEM131L functions as a pivotal checkpoint regulator during thymopoiesis. By modulating both Wnt and Notch pathways, TMEM131L ensures a balanced proliferation arrest and proper developmental progression of thymocytes, highlighting its significance in immune cell lineage commitment and offering insights into potential targets for therapeutic intervention in immune dysregulation.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nesrine Maharzi, Véronique Parietti, Elisabeth Nelson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Identification of TMEM131L as a novel regulator of thymocyte proliferation in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Immunol (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.4049/jimmunol.1300400"}], "href": "https://doi.org/10.4049/jimmunol.1300400"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23690469"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23690469"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Sébastien Szuplewski, Nesrine Maharzi, Elisabeth Nelson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Evolutionary conservation of Notch signaling inhibition by TMEM131L overexpression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem Biophys Res Commun (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbrc.2017.03.123"}], "href": "https://doi.org/10.1016/j.bbrc.2017.03.123"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28347816"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28347816"}]}]}]}