{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nA review of the provided literature on embryonic development—encompassing studies of TGF‐β family signaling, Nodal/Activin activity, and associated regulatory networks—reveals a remarkable depth in our understanding of cell‐fate decisions, axis formation, and stem cell pluripotency. Notably, none of these abstracts describe or characterize SNORD115-3, a small nucleolar RNA normally involved in guiding post‐transcriptional modifications. Its functional contribution to the regulation of these developmental signaling pathways remains unaddressed in this collection of studies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "14"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn contrast, the bulk of these studies dissect intricate mechanisms by which graded Nodal signaling, its interactions with co-receptors such as Cripto, and feedback inhibitors like Lefty and Cerberus orchestrate mesendoderm induction, left–right asymmetry, and other patterning events during early embryogenesis. These works also highlight how downstream effectors (e.g. phosphorylated Smad2/3) and cross-talk with other pathways—including Wnt, BMP, and FGF—achieve both robust stem cell self-renewal and lineage specification. Although SNORD115-3 is not mentioned in any of these reports, its related family members are known for modulating RNA processing; it is conceivable that SNORD115-3, if involved at all, might exert subtle, post‐transcriptional regulatory influences on transcripts coding for key components of these signaling cascades."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "15", "end_ref": "28"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn summary, while these manuscripts collectively advance our understanding of pivotal signaling networks during early vertebrate development and stem cell differentiation, they do not shed light on the role of SNORD115-3. Given that small nucleolar RNAs like SNORD115-3 are primarily involved in guiding chemical modifications of other RNAs, there is an open possibility that future studies may reveal a modulatory role for SNORD115-3 in fine-tuning the expression or splicing of transcripts key to pathways such as Nodal signaling. Such insights would integrate RNA-based regulatory mechanisms into the well-established developmental frameworks explored by these studies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "29", "end_ref": "42"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Caterina Bianco, Heather B Adkins, Christian Wechselberger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cripto-1 activates nodal- and ALK4-dependent and -independent signaling pathways in mammary epithelial Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.22.8.2586-2597.2002"}], "href": "https://doi.org/10.1128/MCB.22.8.2586-2597.2002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11909953"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11909953"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Dominic P Norris, Jane Brennan, Elizabeth K Bikoff, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.129.14.3455"}], "href": "https://doi.org/10.1242/dev.129.14.3455"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12091315"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12091315"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Jane Brennan, Dominic P Norris, Elizabeth J Robertson "}, {"type": "b", "children": [{"type": "t", "text": "Nodal activity in the node governs left-right asymmetry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1016202"}], "href": "https://doi.org/10.1101/gad.1016202"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12231623"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12231623"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Aitana Perea-Gomez, Francis D J Vella, William Shawlot, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal antagonists in the anterior visceral endoderm prevent the formation of multiple primitive streaks."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1534-5807(02)00321-0"}], "href": "https://doi.org/10.1016/s1534-5807(02"}, {"type": "t", "text": "00321-0) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12431380"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12431380"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Séverine Beck, J Ann Le Good, Marcela Guzman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Extraembryonic proteases regulate Nodal signalling during gastrulation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb890"}], "href": "https://doi.org/10.1038/ncb890"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12447384"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12447384"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Rabah Iratni, Yu-Ting Yan, Canhe Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Inhibition of excess nodal signaling during mouse gastrulation by the transcriptional corepressor DRAP1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Science (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/science.1073405"}], "href": "https://doi.org/10.1126/science.1073405"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12471260"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12471260"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yukio Saijoh, Shinya Oki, Sachiko Ohishi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Left-right patterning of the mouse lateral plate requires nodal produced in the node."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0012-1606(02)00121-5"}], "href": "https://doi.org/10.1016/s0012-1606(02"}, {"type": "t", "text": "00121-5) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12654299"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12654299"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Luke T Krebs, Naomi Iwai, Shigenori Nonaka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Notch signaling regulates left-right asymmetry determination by inducing Nodal expression."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1084703"}], "href": "https://doi.org/10.1101/gad.1084703"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12730124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12730124"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Stephane D Vincent, N Ray Dunn, Shigemi Hayashi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cell fate decisions within the mouse organizer are governed by graded Nodal signals."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1100503"}], "href": "https://doi.org/10.1101/gad.1100503"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12842913"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12842913"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Cindy C Lu, Elizabeth J Robertson "}, {"type": "b", "children": [{"type": "t", "text": "Multiple roles for Nodal in the epiblast of the mouse embryo in the establishment of anterior-posterior patterning."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2004.06.004"}], "href": "https://doi.org/10.1016/j.ydbio.2004.06.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15302604"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15302604"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Sara Marques, Ana Cristina Borges, Ana Cristina Silva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The activity of the Nodal antagonist Cerl-2 in the mouse node is required for correct L/R body axis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.306504"}], "href": "https://doi.org/10.1101/gad.306504"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15466485"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15466485"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Marcela Guzman-Ayala, Nadav Ben-Haim, Séverine Beck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal protein processing and fibroblast growth factor 4 synergize to maintain a trophoblast stem cell microenvironment."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0405429101"}], "href": "https://doi.org/10.1073/pnas.0405429101"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15505202"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15505202"}]}, {"type": "r", "ref": 13, "children": [{"type": "t", "text": "Canhe Chen, Stephanie M Ware, Akira Sato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The Vg1-related protein Gdf3 acts in a Nodal signaling pathway in the pre-gastrulation mouse embryo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.02210"}], "href": "https://doi.org/10.1242/dev.02210"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16368929"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16368929"}]}, {"type": "r", "ref": 14, "children": [{"type": "t", "text": "Stephanie M Ware, Karine G Harutyunyan, John W Belmont "}, {"type": "b", "children": [{"type": "t", "text": "Heart defects in X-linked heterotaxy: evidence for a genetic interaction of Zic3 with the nodal signaling pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Dyn (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/dvdy.20719"}], "href": "https://doi.org/10.1002/dvdy.20719"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16496285"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16496285"}]}, {"type": "r", "ref": 15, "children": [{"type": "t", "text": "Olov Andersson, Eva Reissmann, Henrik Jörnvall, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Synergistic interaction between Gdf1 and Nodal during anterior axis development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2006.02.002"}], "href": "https://doi.org/10.1016/j.ydbio.2006.02.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16564040"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16564040"}]}, {"type": "r", "ref": 16, "children": [{"type": "t", "text": "Anne Camus, Aitana Perea-Gomez, Anne Moreau, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Absence of Nodal signaling promotes precocious neural differentiation in the mouse embryo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2006.03.047"}], "href": "https://doi.org/10.1016/j.ydbio.2006.03.047"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16678814"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16678814"}]}, {"type": "r", "ref": 17, "children": [{"type": "t", "text": "Nadav Ben-Haim, Cindy Lu, Marcela Guzman-Ayala, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Cell (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.devcel.2006.07.005"}], "href": "https://doi.org/10.1016/j.devcel.2006.07.005"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16950123"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16950123"}]}, {"type": "r", "ref": 18, "children": [{"type": "t", "text": "Kazuya Ogawa, Akira Saito, Hisanori Matsui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Activin-Nodal signaling is involved in propagation of mouse embryonic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.03296"}], "href": "https://doi.org/10.1242/jcs.03296"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17182901"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17182901"}]}, {"type": "r", "ref": 19, "children": [{"type": "t", "text": "Masanori Takenaga, Miki Fukumoto, Yuichi Hori "}, {"type": "b", "children": [{"type": "t", "text": "Regulated Nodal signaling promotes differentiation of the definitive endoderm and mesoderm from ES cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Sci (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/jcs.004127"}], "href": "https://doi.org/10.1242/jcs.004127"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17535850"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17535850"}]}, {"type": "r", "ref": 20, "children": [{"type": "t", "text": "Shinya Oki, Ryuju Hashimoto, Yuko Okui, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Sulfated glycosaminoglycans are necessary for Nodal signal transmission from the node to the left lateral plate in the mouse embryo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.009464"}], "href": "https://doi.org/10.1242/dev.009464"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17913787"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17913787"}]}, {"type": "r", "ref": 21, "children": [{"type": "t", "text": "Chinatsu Tanaka, Rui Sakuma, Tetsuya Nakamura, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Long-range action of Nodal requires interaction with GDF1."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1623907"}], "href": "https://doi.org/10.1101/gad.1623907"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18079174"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18079174"}]}, {"type": "r", "ref": 22, "children": [{"type": "t", "text": "Jonathan A Kelber, Gidi Shani, Evan C Booker, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Cripto is a noncompetitive activin antagonist that forms analogous signaling complexes with activin and nodal."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M704960200"}], "href": "https://doi.org/10.1074/jbc.M704960200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18089557"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18089557"}]}, {"type": "r", "ref": 23, "children": [{"type": "t", "text": "Erik Willems, Luc Leyns "}, {"type": "b", "children": [{"type": "t", "text": "Patterning of mouse embryonic stem cell-derived pan-mesoderm by Activin A/Nodal and Bmp4 signaling requires Fibroblast Growth Factor activity."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Differentiation (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1432-0436.2007.00257.x"}], "href": "https://doi.org/10.1111/j.1432-0436.2007.00257.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "18177426"}], "href": "https://pubmed.ncbi.nlm.nih.gov/18177426"}]}, {"type": "r", "ref": 24, "children": [{"type": "t", "text": "Masayuki Uehara, Kenta Yashiro, Katsuyoshi Takaoka, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Removal of maternal retinoic acid by embryonic CYP26 is required for correct Nodal expression during early embryonic patterning."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genes Dev (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1101/gad.1776209"}], "href": "https://doi.org/10.1101/gad.1776209"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19605690"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19605690"}]}, {"type": "r", "ref": 25, "children": [{"type": "t", "text": "Zuping He, Jiji Jiang, Maria Kokkinaki, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal signaling via an autocrine pathway promotes proliferation of mouse spermatogonial stem/progenitor cells through Smad2/3 and Oct-4 activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.198"}], "href": "https://doi.org/10.1002/stem.198"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19688838"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19688838"}]}, {"type": "r", "ref": 26, "children": [{"type": "t", "text": "Katherine E Galvin, Emily D Travis, Della Yee, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal signaling regulates the bone morphogenic protein pluripotency pathway in mouse embryonic stem cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M109.077347"}], "href": "https://doi.org/10.1074/jbc.M109.077347"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20427282"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20427282"}]}, {"type": "r", "ref": 27, "children": [{"type": "t", "text": "Øyvind Dahle, Amit Kumar, Michael R Kuehn "}, {"type": "b", "children": [{"type": "t", "text": "Nodal signaling recruits the histone demethylase Jmjd3 to counteract polycomb-mediated repression at target genes."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Sci Signal (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1126/scisignal.2000841"}], "href": "https://doi.org/10.1126/scisignal.2000841"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20571128"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20571128"}]}, {"type": "r", "ref": 28, "children": [{"type": "t", "text": "Nina Engberg, Morten Kahn, Dorthe Rønn Petersen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Retinoic acid synthesis promotes development of neural progenitors from mouse embryonic stem cells by suppressing endogenous, Wnt-dependent nodal signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.479"}], "href": "https://doi.org/10.1002/stem.479"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20665854"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20665854"}]}, {"type": "r", "ref": 29, "children": [{"type": "t", "text": "Céline Granier, Vasily Gurchenkov, Aitana Perea-Gomez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal cis-regulatory elements reveal epiblast and primitive endoderm heterogeneity in the peri-implantation mouse embryo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Dev Biol (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ydbio.2010.10.036"}], "href": "https://doi.org/10.1016/j.ydbio.2010.10.036"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21047506"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21047506"}]}, {"type": "r", "ref": 30, "children": [{"type": "t", "text": "Kian Leong Lee, Sandy Keat Lim, Yuriy Lvovich Orlov, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Graded Nodal/Activin signaling titrates conversion of quantitative phospho-Smad2 levels into qualitative embryonic stem cell fate decisions."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS Genet (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pgen.1002130"}], "href": "https://doi.org/10.1371/journal.pgen.1002130"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21731500"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21731500"}]}, {"type": "r", "ref": 31, "children": [{"type": "t", "text": "Enza Lonardo, Patrick C Hermann, Maria-Theresa Mueller, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2011.10.001"}], "href": "https://doi.org/10.1016/j.stem.2011.10.001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22056140"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22056140"}]}, {"type": "r", "ref": 32, "children": [{"type": "t", "text": "Benoit Souquet, Sophie Tourpin, Sébastien Messiaen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal signaling regulates the entry into meiosis in fetal germ cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Endocrinology (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1210/en.2011-2056"}], "href": "https://doi.org/10.1210/en.2011-2056"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22396454"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22396454"}]}, {"type": "r", "ref": 33, "children": [{"type": "t", "text": "Cassy M Spiller, Chun-Wei Feng, Andrew Jackson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Endogenous Nodal signaling regulates germ cell potency during mammalian testis development."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.083006"}], "href": "https://doi.org/10.1242/dev.083006"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23034635"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23034635"}]}, {"type": "r", "ref": 34, "children": [{"type": "t", "text": "Katherine E Galvin-Burgess, Emily D Travis, Kelsey E Pierson, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TGF-β-superfamily signaling regulates embryonic stem cell heterogeneity: self-renewal as a dynamic and regulated equilibrium."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cells (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/stem.1252"}], "href": "https://doi.org/10.1002/stem.1252"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23081664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23081664"}]}, {"type": "r", "ref": 35, "children": [{"type": "t", "text": "Quan Wu, Kohei Kanata, Rie Saba, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Nodal/activin signaling promotes male germ cell fate and suppresses female programming in somatic cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Development (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1242/dev.087882"}], "href": "https://doi.org/10.1242/dev.087882"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23221368"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23221368"}]}, {"type": "r", "ref": 36, "children": [{"type": "t", "text": "Hidetaka Shiratori, Hiroshi Hamada "}, {"type": "b", "children": [{"type": "t", "text": "TGFβ signaling in establishing left-right asymmetry."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Semin Cell Dev Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.semcdb.2014.03.029"}], "href": "https://doi.org/10.1016/j.semcdb.2014.03.029"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24704359"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24704359"}]}, {"type": "r", "ref": 37, "children": [{"type": "t", "text": "Elizabeth J Robertson "}, {"type": "b", "children": [{"type": "t", "text": "Dose-dependent Nodal/Smad signals pattern the early mouse embryo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Semin Cell Dev Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.semcdb.2014.03.028"}], "href": "https://doi.org/10.1016/j.semcdb.2014.03.028"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24704361"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24704361"}]}, {"type": "r", "ref": 38, "children": [{"type": "t", "text": "Julien Dubrulle, Benjamin M Jordan, Laila Akhmetova, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Response to Nodal morphogen gradient is determined by the kinetics of target gene induction."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2015)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.05042"}], "href": "https://doi.org/10.7554/eLife.05042"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25869585"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25869585"}]}, {"type": "r", "ref": 39, "children": [{"type": "t", "text": "Hai-Qiang Dai, Bang-An Wang, Lu Yang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "TET-mediated DNA demethylation controls gastrulation by regulating Lefty-Nodal signalling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature20095"}], "href": "https://doi.org/10.1038/nature20095"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27760115"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27760115"}]}, {"type": "r", "ref": 40, "children": [{"type": "t", "text": "Qiong Wang, Yilong Zou, Sonja Nowotschin, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The p53 Family Coordinates Wnt and Nodal Inputs in Mesendodermal Differentiation of Embryonic Stem Cells."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Stem Cell (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stem.2016.10.002"}], "href": "https://doi.org/10.1016/j.stem.2016.10.002"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27889317"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27889317"}]}, {"type": "r", "ref": 41, "children": [{"type": "t", "text": "Carla Mulas, Tüzer Kalkan, Austin Smith "}, {"type": "b", "children": [{"type": "t", "text": "NODAL Secures Pluripotency upon Embryonic Stem Cell Progression from the Ground State."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Stem Cell Reports (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.stemcr.2017.05.033"}], "href": "https://doi.org/10.1016/j.stemcr.2017.05.033"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28669603"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28669603"}]}, {"type": "r", "ref": 42, "children": [{"type": "t", "text": "Tessa G Montague, Alexander F Schier "}, {"type": "b", "children": [{"type": "t", "text": "Vg1-Nodal heterodimers are the endogenous inducers of mesendoderm."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Elife (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.7554/eLife.28183"}], "href": "https://doi.org/10.7554/eLife.28183"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29140251"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29140251"}]}]}]}