{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Growth/differentiation factor 1 (GDF1) is a member of the transforming growth factor‐β superfamily that plays a central role in embryonic development, particularly in establishing left–right asymmetry and orchestrating cardiac morphogenesis. Functional and genetic studies have demonstrated that GDF1 acts within the Nodal signaling pathway—often in cooperation with co‐receptors such as Cripto—to potentiate TGF‐β–mediated signals that are essential for proper heart development and laterality specification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": " In this context, GDF1 can heterodimerize with Nodal to stabilize a low molecular weight signaling complex that enhances receptor activation and downstream transcriptional programs involved in stem cell differentiation and mesoderm specification."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, environmental factors such as arsenic exposure have been shown to downregulate GDF1 expression via oxidative stress–mediated mechanisms, thereby contributing to abnormal cardiac development."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Genetic studies further underscore its importance, as both coding and regulatory variants in GDF1 have been implicated in increased susceptibility to congenital heart defects—including conditions such as tetralogy of Fallot, conotruncal defects, and heterotaxy—through mechanisms affecting ligand function or promoter activity (mediated, for example, by Nkx2.5)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings highlight that GDF1 is a critical modulator of early embryogenesis, linking proper Nodal/TGF‐β signaling with the development of the heart and the establishment of left–right body asymmetry. Disruptions in its expression or function not only elucidate the molecular basis of congenital heart disease but also offer potential avenues for targeted interventions and genetic risk assessment.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Erich Roessler, Maia V Ouspenskaia, Jayaprakash D Karkera, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2008.05.012"}], "href": "https://doi.org/10.1016/j.ajhg.2008.05.012"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18538293"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18538293"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J D Karkera, J S Lee, E Roessler, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Loss-of-function mutations in growth differentiation factor-1 (GDF1) are associated with congenital heart defects in humans."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1086/522890"}], "href": "https://doi.org/10.1086/522890"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17924340"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17924340"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Peter C Gray, Gidi Shani, Kevin Aung, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cripto binds transforming growth factor beta (TGF-beta) and inhibits TGF-beta signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01168-06"}], "href": "https://doi.org/10.1128/MCB.01168-06"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17030617"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17030617"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Christophe Fuerer, M Cristina Nostro, Daniel B Constam "}, {"type": "b", "children": [{"type": "t", "text": "Nodal·Gdf1 heterodimers with bound prodomains enable serum-independent nodal signaling and endoderm differentiation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M114.550301"}], "href": "https://doi.org/10.1074/jbc.M114.550301"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24798330"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24798330"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Seung-Cheol Choi, Ji-Hyun Choi, Long-Hui Cui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mixl1 and Flk1 Are Key Players of Wnt/TGF-β Signaling During DMSO-Induced Mesodermal Specification in P19 cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Physiol (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jcp.24892"}], "href": "https://doi.org/10.1002/jcp.24892"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25521758"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25521758"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Xiaobo Gao, Chen Zhang, Panpan Zheng, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Arsenic suppresses GDF1 expression via ROS-dependent downregulation of specificity protein 1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Environ Pollut (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.envpol.2020.116302"}], "href": "https://doi.org/10.1016/j.envpol.2020.116302"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "33360347"}], "href": "https://pubmed.ncbi.nlm.nih.gov/33360347"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Juan Zhang, Qingqing Wu, Li Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of GDF1 rs4808863 with fetal congenital heart defects: a case-control study."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "BMJ Open (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1136/bmjopen-2015-009352"}], "href": "https://doi.org/10.1136/bmjopen-2015-009352"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "26656983"}], "href": "https://pubmed.ncbi.nlm.nih.gov/26656983"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Xiaowei Sun, Ying Meng, Tao You, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of growth/differentiation factor 1 gene polymorphisms with the risk of congenital heart disease in the Chinese Han population."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Rep (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s11033-012-2172-0"}], "href": "https://doi.org/10.1007/s11033-012-2172-0"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23076529"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23076529"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Dina Marek-Yagel, Yoav Bolkier, Ortal Barel, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A founder truncating variant in GDF1 causes autosomal-recessive right isomerism and associated congenital heart defects in multiplex Arab kindreds."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Med Genet A (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/ajmg.a.61509"}], "href": "https://doi.org/10.1002/ajmg.a.61509"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32144877"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32144877"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Xiaobo Gao, Panpan Zheng, Liping Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Association of functional variant in GDF1 promoter with risk of congenital heart disease and its regulation by Nkx2.5."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Clin Sci (Lond) (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/CS20181024"}], "href": "https://doi.org/10.1042/CS20181024"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31171573"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31171573"}]}]}]}