{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T15:01:44Z","timestamp":1770562904549,"version":"3.49.0"},"reference-count":36,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,4,29]],"date-time":"2023-04-29T00:00:00Z","timestamp":1682726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Vision is likely our most prominent sense and a correct development of the eye is at its basis. Early eye development is tightly connected to the development of the forebrain. A single eye field and the prospective telencephalon are situated within the anterior neural plate (ANP). During normal development, both domains are split and consecutively, two optic vesicles and two telencephalic lobes emerge. If this process is hampered, the domains remain condensed at the midline. The resulting developmental disorder is termed holoprosencephaly (HPE). The typical ocular finding associated with intense forms of HPE is cyclopia. However, also anophthalmia and coloboma can be associated with HPE. Here, we report that a correct balance of Bone morphogenetic proteins (BMPs) and their antagonists are important for forebrain and eye field cleavage. Experimental induction of a BMP ligand results in a severe form of HPE showing anophthalmia. We identified a dysmorphic forebrain containing retinal progenitors, which we termed crypt-oculoid. Optic vesicle evagination is impaired due to a loss of rx3 and, consecutively, of cxcr4a. Our data further suggest that the subduction of prospective hypothalamic cells during neurulation and neural keel formation is affected by the induction of a BMP ligand.<\/jats:p>","DOI":"10.3390\/ijms24098052","type":"journal-article","created":{"date-parts":[[2023,5,1]],"date-time":"2023-05-01T13:54:46Z","timestamp":1682949286000},"page":"8052","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Holoprosencephaly with a Special Form of Anophthalmia Result from Experimental Induction of bmp4, Oversaturating BMP Antagonists in Zebrafish"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-4637-2427","authenticated-orcid":false,"given":"Johannes","family":"Bulk","sequence":"first","affiliation":[{"name":"Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valentyn","family":"Kyrychenko","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp M.","family":"Rensinghoff","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zahra","family":"Ghaderi Ardekani","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan","family":"Heermann","sequence":"additional","affiliation":[{"name":"Department of Molecular Embryology, Institute of Anatomy and Cell Biology, Faculty of Medicine, University Freiburg, 79104 Freiburg, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,4,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1130","DOI":"10.1126\/science.1127144","article-title":"Individual Cell Migration Serves as the Driving Force for Optic Vesicle Evagination","volume":"313","author":"Rembold","year":"2006","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.ydbio.2009.12.003","article-title":"Nlcam Modulates Midline Convergence during Anterior Neural Plate Morphogenesis","volume":"339","author":"Brown","year":"2010","journal-title":"Dev. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"812","DOI":"10.1016\/j.devcel.2012.09.006","article-title":"BMP Signaling Protects Telencephalic Fate by Repressing Eye Identity and Its Cxcr4-Dependent Morphogenesis","volume":"23","author":"Bielen","year":"2012","journal-title":"Dev. Cell"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"4613","DOI":"10.1242\/dev.02678","article-title":"A Dynamic Fate Map of the Forebrain Shows How Vertebrate Eyes Form and Explains Two Causes of Cyclopia","volume":"133","author":"England","year":"2006","journal-title":"Development"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1002\/ajmg.c.31623","article-title":"Neuropathology of Holoprosencephaly","volume":"178","year":"2018","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1038\/383407a0","article-title":"Cyclopia and Defective Axial Patterning in Mice Lacking Sonic Hedgehog Gene Function","volume":"383","author":"Chiang","year":"1996","journal-title":"Nature"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1038\/ng1196-357","article-title":"Mutations in the Human Sonic Hedgehog Gene Cause Holoprosencephaly","volume":"14","author":"Roessler","year":"1996","journal-title":"Nat. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0896-6273(02)00751-1","article-title":"Establishment of the Telencephalon during Gastrulation by Local Antagonism of Wnt Signaling","volume":"35","author":"Houart","year":"2002","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1002\/dneu.22135","article-title":"Integration of Anterior Neural Plate Patterning and Morphogenesis by the Wnt Signaling Pathway","volume":"74","author":"Cavodeassi","year":"2014","journal-title":"Dev. Neurobiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1038\/35001072","article-title":"The Organizer Factors Chordin and Noggin Are Required for Mouse Forebrain Development","volume":"403","author":"Bachiller","year":"2000","journal-title":"Nature"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1016\/j.devcel.2005.01.013","article-title":"Depletion of Three BMP Antagonists from Spemann\u2019s Organizer Leads to a Catastrophic Loss of Dorsal Structures","volume":"8","author":"Khokha","year":"2005","journal-title":"Dev. Cell"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"180179","DOI":"10.1098\/rsob.180179","article-title":"Morphogenesis and Axis Specification Occur in Parallel during Optic Cup and Optic Fissure Formation, Differentially Modulated by BMP and Wnt","volume":"9","author":"Eckert","year":"2019","journal-title":"Open. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e05216","DOI":"10.7554\/eLife.05216","article-title":"Eye Morphogenesis Driven by Epithelial Flow into the Optic Cup Facilitated by Modulation of Bone Morphogenetic Protein","volume":"4","author":"Heermann","year":"2015","journal-title":"eLife"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"170134","DOI":"10.1098\/rsob.170134","article-title":"TGF\u03b2-Facilitated Optic Fissure Fusion and the Role of Bone Morphogenetic Protein Antagonism","volume":"8","author":"Knickmeyer","year":"2018","journal-title":"Open Biol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Eckert, P., Knickmeyer, M.D., and Heermann, S. (2020). In Vivo Analysis of Optic Fissure Fusion in Zebrafish: Pioneer Cells, Basal Lamina, Hyaloid Vessels, and How Fissure Fusion Is Affected by BMP. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21082760"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"482","DOI":"10.3389\/fped.2019.00482","article-title":"FOXG1 Dose in Brain Development","volume":"7","author":"Hettige","year":"2019","journal-title":"Front. Pediatr."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5229","DOI":"10.1523\/JNEUROSCI.1134-08.2008","article-title":"Foxg1 Is Required for Development of the Vertebrate Olfactory System","volume":"28","author":"Duggan","year":"2008","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"894","DOI":"10.1038\/sj.embor.embor919","article-title":"Loss of eyes in zebrafish caused by mutation of chokh\/rx3","volume":"4","author":"Loosli","year":"2003","journal-title":"EMBO Rep."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4035","DOI":"10.1242\/dev.128.20.4035","article-title":"Medaka Eyeless Is the Key Factor Linking Retinal Determination and Eye Growth","volume":"128","author":"Loosli","year":"2001","journal-title":"Development"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.devcel.2018.06.003","article-title":"A Rapid Method for Directed Gene Knockout for Screening in G0 Zebrafish","volume":"46","author":"Wu","year":"2018","journal-title":"Dev. Cell."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2986","DOI":"10.1093\/hmg\/ddn197","article-title":"Zic2 -Associated Holoprosencephaly Is Caused by a Transient Defect in the Organizer Region during Gastrulation","volume":"17","author":"Warr","year":"2008","journal-title":"Hum. Mol. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3791","DOI":"10.1242\/dev.037820","article-title":"Zebrafish Zic2a Patterns the Forebrain through Modulation of Hedgehog-Activated Gene Expression","volume":"136","author":"Sanek","year":"2009","journal-title":"Development"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1242\/dev.124.3.603","article-title":"A Single Morphogenetic Field Gives Rise to Two Retina Primordia under the Influence of the Prechordal Plate","volume":"124","author":"Li","year":"1997","journal-title":"Development"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"23636","DOI":"10.1073\/pnas.1901732116","article-title":"SHH Signaling Mediated by a Prechordal and Brain Enhancer Controls Forebrain Organization","volume":"116","author":"Sagai","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1146\/annurev.cellbio.17.1.255","article-title":"Early Eye Development in Vertebrates","volume":"17","author":"Chow","year":"2001","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_26","first-page":"76","article-title":"march5 Governs the Convergence and Extension Movement for Organization of the Telencephalon and Diencephalon in Zebrafish Embryos","volume":"43","author":"Jung","year":"2020","journal-title":"Mol. Cells"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ydbio.2009.04.022","article-title":"Apc1 Is Required for Maintenance of Local Brain Organizers and Dorsal Midbrain Survival","volume":"331","author":"Paridaen","year":"2009","journal-title":"Dev. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1002\/tera.1420160304","article-title":"Holoprosencephaly in Human Embryos: Epidemiologic Studies of 150 Cases","volume":"16","author":"Matsunaga","year":"1977","journal-title":"Teratology"},{"key":"ref_29","first-page":"2713","article-title":"A Broad Range of Ophthalmologic Anomalies Is Part of the Holoprosencephaly Spectrum","volume":"155A","author":"Solomon","year":"2011","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1002\/ajmg.c.31615","article-title":"Holoprosencephaly in the Genomics Era","volume":"178","author":"Roessler","year":"2018","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1002\/aja.1002030302","article-title":"Stages of Embryonic Development of the Zebrafish","volume":"203","author":"Kimmel","year":"1995","journal-title":"Dev. Dyn."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1002\/dvdy.22567","article-title":"Dynamic Smad-Mediated BMP Signaling Revealed through Transgenic Zebrafish","volume":"240","author":"Collery","year":"2011","journal-title":"Dev. Dyn."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An Open-Source Platform for Biological-Image Analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"971","DOI":"10.1016\/j.mod.2004.03.031","article-title":"Large-Scale Expression Screening by Automated Whole-Mount in Situ Hybridization","volume":"121","author":"Quiring","year":"2004","journal-title":"Mech. Dev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3389\/fnins.2018.00266","article-title":"A PCR-Based Method for RNA Probes and Applications in Neuroscience","volume":"12","author":"Hua","year":"2018","journal-title":"Front. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Stemmer, M., Thumberger, T., del Sol Keyer, M., Wittbrodt, J., and Mateo, J.L. (2015). CCTop: An Intuitive, Flexible and Reliable CRISPR\/Cas9 Target Prediction Tool. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124633"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8052\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:26:25Z","timestamp":1760124385000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/9\/8052"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,29]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,5]]}},"alternative-id":["ijms24098052"],"URL":"https:\/\/doi.org\/10.3390\/ijms24098052","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,29]]}}}