{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T15:18:11Z","timestamp":1787584691814,"version":"build-2736575974"},"reference-count":91,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T00:00:00Z","timestamp":1753401600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JDB"],"abstract":"<jats:p>Craniofacial development is a complex, highly conserved process involving multiple tissue types and molecular pathways, with perturbations resulting in congenital defects that often require invasive surgical interventions to correct. Remarkably, some species, such as Xenopus laevis, can correct some craniofacial abnormalities during pre-metamorphic stages through thyroid hormone-independent mechanisms. However, the full scope of factors mediating remodeling initiation and coordination remain unclear. This study explores the differential remodeling responses of craniofacial defects by comparing the effects of two pharmacological agents, thioridazine-hydrochloride (thio) and ivermectin (IVM), on craniofacial morphology in X. laevis. Thio-exposure reliably induces a craniofacial defect that can remodel in pre-metamorphic animals, while IVM induces a permanent, non-correcting phenotype. We examined developmental changes from feeding stages to hindlimb bud stages and mapped the effects of each agent on the patterning of craniofacial tissue types including: cartilage, muscle, and nerves. Our findings reveal that thio-induced craniofacial defects exhibit significant consistent remodeling, particularly in muscle, with gene expression analysis revealing upregulation of key remodeling genes, matrix metalloproteinases 1 and 13, as well as their regulator, prolactin.2. In contrast, IVM-induced defects show no significant remodeling, highlighting the importance of specific molecular and cellular factors in pre-metamorphic craniofacial correction. Additionally, unique neuronal profiles suggest a previously underappreciated role for the nervous system in tissue remodeling. This study provides novel insights into the molecular and cellular mechanisms underlying craniofacial defect remodeling and lays the groundwork for future investigations into tissue repair in vertebrates.<\/jats:p>","DOI":"10.3390\/jdb13030026","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T11:38:41Z","timestamp":1753443521000},"page":"26","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Identification and Characterization of Static Craniofacial Defects in Pre-Metamorphic Xenopus laevis Tadpoles"],"prefix":"10.3390","volume":"13","author":[{"given":"Emilie","family":"Jones","sequence":"first","affiliation":[{"name":"Department of Biology, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9910-1933","authenticated-orcid":false,"given":"Jay Miguel","family":"Fonticella","sequence":"additional","affiliation":[{"name":"Department of Biology, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly A.","family":"McLaughlin","sequence":"additional","affiliation":[{"name":"Department of Biology, Tufts University, Medford, MA 02155, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,25]]},"reference":[{"key":"ref_1","unstructured":"(2024, October 11). CDC Data and Statistics on Birth Defects, Available online: https:\/\/www.cdc.gov\/birth-defects\/data-research\/facts-stats\/index.html."},{"key":"ref_2","unstructured":"(2024, October 11). CDC Cleft Lip\/Cleft Palate, Available online: https:\/\/www.cdc.gov\/birth-defects\/about\/cleft-lip-cleft-palate.html."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1016\/bs.ctdb.2015.07.003","article-title":"From Bench to Bedside and Back: Improving Diagnosis and Treatment of Craniofacial Malformations Utilizing Animal Models","volume":"115","author":"Goodwin","year":"2015","journal-title":"Curr. Top. Dev. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1002\/dvdy.672","article-title":"Wnt10a Is Required for Zebrafish Median Fin Fold Maintenance and Adult Unpaired Fin Metamorphosis","volume":"253","author":"Benard","year":"2024","journal-title":"Dev. Dyn."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2975","DOI":"10.1002\/dvdy.22113","article-title":"Normal Table of Postembryonic Zebrafish Development: Staging by Externally Visible Anatomy of the Living Fish","volume":"238","author":"Parichy","year":"2009","journal-title":"Dev. Dyn."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Shi, Y., Yang, S., Ji, W., Li, X., Shi, Z., Hou, J., Li, W., and Fu, Y. (2023). Thyroid Hormone Signaling Is Required for Dynamic Variation in Opsins in the Retina during Metamorphosis of the Japanese Flounder (Paralichthys Olivaceus). Biology, 12.","DOI":"10.3390\/biology12030397"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1139\/cjz-2012-0240","article-title":"Expression of Genes Involved in Key Metabolic Processes during Winter Flounder (Pseudopleuronectes Americanus) Metamorphosis","volume":"91","author":"Vagner","year":"2013","journal-title":"Can. J. Zool."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"110898","DOI":"10.1016\/j.isci.2024.110898","article-title":"Developmental Correspondence of Juvenile Stages across the Locust, Harlequin Ladybird, and Diamondback Moth","volume":"27","author":"Zhou","year":"2024","journal-title":"iScience"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"dev175893","DOI":"10.1242\/dev.175893","article-title":"Adaptive Correction of Craniofacial Defects in Pre-Metamorphic Xenopus Laevis Tadpoles Involves Thyroid Hormone-Independent Tissue Remodeling","volume":"146","author":"Pinet","year":"2019","journal-title":"Development"},{"key":"ref_10","unstructured":"Nieuwkoop, P.D., and Faber, E.J. (1967). Normal Table of Xenopus Laevis (DAUDIN): A Systematical and Chronological Survey of the Development from the Fertilized Egg Till the End of Metamorphosis, Garland Science."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1002\/dvdy.23770","article-title":"Normalized Shape and Location of Perturbed Craniofacial Structures in the Xenopus Tadpole Reveal an Innate Ability to Achieve Correct Morphology","volume":"241","author":"Vandenberg","year":"2012","journal-title":"Dev. Dyn."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1002\/dvdy.20276","article-title":"XTbx1 Is a Transcriptional Activator Involved in Head and Pharyngeal Arch Development in Xenopus Laevis","volume":"232","author":"Ataliotis","year":"2005","journal-title":"Dev. Dyn."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.ydbio.2016.02.010","article-title":"Sf3b4-Depleted Xenopus Embryos: A Model to Study the Pathogenesis of Craniofacial Defects in Nager Syndrome","volume":"415","author":"Devotta","year":"2016","journal-title":"Dev. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.semcdb.2016.01.016","article-title":"Using Frogs Faces to Dissect the Mechanisms Underlying Human Orofacial Defects","volume":"51","author":"Dickinson","year":"2016","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1016\/j.ydbio.2012.02.033","article-title":"Median Facial Clefts in Xenopus Laevis: Roles of Retinoic Acid Signaling and Homeobox Genes","volume":"365","author":"Kennedy","year":"2012","journal-title":"Dev. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Slater, B.J., Liu, K.J., Kwan, M.D., Quarto, N., and Longaker, M.T. (2009). Cranial Osteogenesis and Suture Morphology in Xenopus Laevis: A Unique Model System for Studying Craniofacial Development. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0003914"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1495","DOI":"10.1126\/science.1118435","article-title":"ATP Signaling Is Crucial for Communication from Taste Buds to Gustatory Nerves","volume":"310","author":"Finger","year":"2005","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1111\/j.1600-079X.2004.00160.x","article-title":"Comparison of Target Innervation by Sympathetic Axons in Adult Wild Type and Heterozygous Mice for Nerve Growth Factor or Its Receptor trkA","volume":"37","author":"Ghasemlou","year":"2004","journal-title":"J. Pineal Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ydbio.2008.07.016","article-title":"Development and Tissue Origins of the Mammalian Cranial Base","volume":"322","author":"Iseki","year":"2008","journal-title":"Dev. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1038\/s41467-024-46396-4","article-title":"Dynamic Enhancer Landscapes in Human Craniofacial Development","volume":"15","author":"Rajderkar","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1519","DOI":"10.1242\/dev.029090","article-title":"Fate Mapping of Mammalian Embryonic Taste Bud Progenitors","volume":"136","author":"Thirumangalathu","year":"2009","journal-title":"Development"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1002\/jor.21014","article-title":"The Role of Muscle Cells in Regulating Cartilage Matrix Production","volume":"28","author":"Cairns","year":"2010","journal-title":"J. Orthop. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.ydbio.2004.09.038","article-title":"Motoneurons Regulate Myoblast Proliferation and Patterning in Drosophila","volume":"277","author":"Fernandes","year":"2005","journal-title":"Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Roddy, K.A., Prendergast, P.J., and Murphy, P. (2011). Mechanical Influences on Morphogenesis of the Knee Joint Revealed through Morphological, Molecular and Computational Analysis of Immobilised Embryos. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0017526"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1002\/jmor.20208","article-title":"Development of the Trigeminal Motor Neurons in Parrots: Implications for the Role of Nervous Tissue in the Evolution of Jaw Muscle Morphology","volume":"275","author":"Tokita","year":"2014","journal-title":"J. Morphol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"5068","DOI":"10.1210\/en.2012-1463","article-title":"Thyroid Hormone Signaling in the Xenopus Laevis Embryo Is Functional and Susceptible to Endocrine Disruption","volume":"153","author":"Fini","year":"2012","journal-title":"Endocrinology"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Paul, B., Sterner, Z.R., Buchholz, D.R., Shi, Y.-B., and Sachs, L.M. (2022). Thyroid and Corticosteroid Signaling in Amphibian Metamorphosis. Cells, 11.","DOI":"10.3390\/cells11101595"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1046\/j.1524-475X.1998.60407.x","article-title":"Thyroid Hormone Regulation of Xenopus Laevis Metamorphosis: Functions of Thyroid Hormone Receptors and Roles of Extracellular Matrix Remodeling","volume":"6","author":"Shi","year":"1998","journal-title":"Wound Repair Regen."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"5610","DOI":"10.1210\/en.2008-0751","article-title":"Developmental Regulation and Function of Thyroid Hormone Receptors and 9-Cis Retinoic Acid Receptors during Xenopus Tropicalis Metamorphosis","volume":"149","author":"Wang","year":"2008","journal-title":"Endocrinology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Wen, L., He, C., Sifuentes, C.J., and Denver, R.J. (2019). Thyroid Hormone Receptor Alpha Is Required for Thyroid Hormone-Dependent Neural Cell Proliferation During Tadpole Metamorphosis. Front. Endocrinol., 10.","DOI":"10.3389\/fendo.2019.00396"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1080\/08820139.2021.1936012","article-title":"Prolactin Protects the Structural Integrity of Human Fetal Membranes by Downregulating Inflammation-Induced Secretion of Matrix Metalloproteinases","volume":"51","year":"2022","journal-title":"Immunol. Investig."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.theriogenology.2021.04.002","article-title":"Response of the Matrix Metalloproteinase System of the Chicken Ovary to Prolactin Treatment","volume":"169","author":"Hrabia","year":"2021","journal-title":"Theriogenology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1073\/pnas.97.1.195","article-title":"Prolactin Is Not a Juvenile Hormone in Xenopus Laevis Metamorphosis","volume":"97","author":"Huang","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"177","DOI":"10.3109\/14756366.2016.1161620","article-title":"Matrix Metalloproteinases (MMPs), the Main Extracellular Matrix (ECM) Enzymes in Collagen Degradation, as a Target for Anticancer Drugs","volume":"31","author":"Matejczyk","year":"2016","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/jcp.20037","article-title":"Activity and Expression of Xenopus Laevis Matrix Metalloproteinases: Identification of a Novel Role for the Hormone Prolactin in Regulating Collagenolysis in Both Amphibians and Mammals","volume":"201","author":"Jung","year":"2004","journal-title":"J. Cell. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.cbpc.2008.05.010","article-title":"Prolactin-Dependent Modulation of Organogenesis in the Vertebrate: Recent Discoveries in Zebrafish","volume":"148","author":"Nguyen","year":"2008","journal-title":"Comp. Biochem. Physiol. Part C Toxicol. Pharmacol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3559","DOI":"10.1074\/jbc.M111.265744","article-title":"E74-like Factor 3 (ELF3) Impacts on Matrix Metalloproteinase 13 (MMP13) Transcriptional Control in Articular Chondrocytes under Proinflammatory Stress","volume":"287","author":"Otero","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.matbio.2015.03.002","article-title":"Matrix Remodeling by MMPs during Wound Repair","volume":"44\u201346","author":"Rohani","year":"2015","journal-title":"Matrix Biol."},{"key":"ref_39","unstructured":"Sive, H., Grainger, R., and Harland, R. (2000). Early Development of Xe-Nopus Laevis: A Laboratory Manual, Springer."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1111\/2041-210X.12326","article-title":"StereoMorph: An R Package for the Collection of 3D Landmarks and Curves Using a Stereo Camera Set-Up","volume":"6","author":"Olsen","year":"2015","journal-title":"Methods Ecol. Evol."},{"key":"ref_41","first-page":"9","article-title":"Knockdown of Zax in Xenopus Laevis Leads to Craniofacial Malformations and the Absence of the Intramandibular Joint","volume":"70","author":"Lukas","year":"2019","journal-title":"Vertebr. Zool."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Deniz, E., Jonas, S., Hooper, M., N.Griffin, J., Choma, M.A., and Khokha, M.K. (2017). Analysis of Craniocardiac Malformations in Xenopus Using Optical Coherence Tomography. Sci. Rep., 7.","DOI":"10.1038\/srep42506"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Lukas, P., and Ziermann, J.M. (2022). Sequence of Chondrocranial Development in Basal Anurans\u2014Let\u2019s Make a Cranium. Front. Zool., 19.","DOI":"10.1186\/s12983-022-00462-z"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1340","DOI":"10.1002\/dvdy.465","article-title":"Normal Development in Xenopus Laevis: A Complementary Staging Table for the Skull Based on Cartilage and Bone","volume":"251","author":"MacKenzie","year":"2022","journal-title":"Dev. Dyn."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Rose, C.S. (2023). The Cellular Basis of Cartilage Growth and Shape Change in Larval and Metamorphosing Xenopus Frogs. PLoS ONE, 18.","DOI":"10.1371\/journal.pone.0277110"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1146\/annurev.biochem.75.103004.142622","article-title":"Signaling Pathways in Skeletal Muscle Remodeling","volume":"75","author":"Olson","year":"2006","journal-title":"Annu. Rev. Biochem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1089\/ars.2013.5773","article-title":"Exercise-Induced Skeletal Muscle Remodeling and Metabolic Adaptation: Redox Signaling and Role of Autophagy","volume":"21","author":"Ferraro","year":"2014","journal-title":"Antioxid. Redox Signal"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1242\/jeb.050112","article-title":"Muscle Damage and Muscle Remodeling: No Pain, No Gain?","volume":"214","author":"Flann","year":"2011","journal-title":"J. Exp. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1126\/science.1076647","article-title":"Pregnancy-Stimulated Neurogenesis in the Adult Female Forebrain Mediated by Prolactin","volume":"299","author":"Shingo","year":"2003","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1523\/JNEUROSCI.3178-08.2009","article-title":"Prolactin Prevents Chronic Stress-Induced Decrease of Adult Hippocampal Neurogenesis and Promotes Neuronal Fate","volume":"29","author":"Torner","year":"2009","journal-title":"J. Neurosci."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Walker, T.L., Vukovic, J., Koudijs, M.M., Blackmore, D.G., Mackay, E.W., Sykes, A.M., Overall, R.W., Hamlin, A.S., and Bartlett, P.F. (2012). Prolactin Stimulates Precursor Cells in the Adult Mouse Hippocampus. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044371"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/nrm2125","article-title":"Matrix Metalloproteinases and the Regulation of Tissue Remodelling","volume":"8","author":"Ewald","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1080\/03008207.2020.1862806","article-title":"Differential MMP 1 and MMP 13 Expression in Proliferation and Ligamentization Phases of Graft Remodeling in Anterior Cruciate Ligament Reconstruction","volume":"62","author":"Yung","year":"2021","journal-title":"Connect. Tissue Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1111\/1523-1747.ep12276722","article-title":"Distinct Populations of Stromal Cells Express Collagenase-3 (MMP-13) and Collagenase-1 (MMP-1) in Chronic Ulcers but Not in Normally Healing Wounds","volume":"109","author":"Vaalamo","year":"1997","journal-title":"J. Investig. Dermatol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/ar401","article-title":"Transcriptional Regulation of Collagenase (MMP-1, MMP-13) Genes in Arthritis: Integration of Complex Signaling Pathways for the Recruitment of Gene-Specific Transcription Factors","volume":"4","author":"Vincenti","year":"2002","journal-title":"Arthritis Res. Ther."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1007\/s13311-014-0317-7","article-title":"A Novel Method for Inducing Nerve Growth via Modulation of Host Resting Potential: Gap Junction-Mediated and Serotonergic Signaling Mechanisms","volume":"12","author":"Blackiston","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"12392","DOI":"10.1021\/acsomega.8b01451","article-title":"Ivermectin Promotes Peripheral Nerve Regeneration during Wound Healing","volume":"3","author":"Cairns","year":"2018","journal-title":"ACS Omega"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"558e","DOI":"10.1097\/PRS.0b013e318262f26b","article-title":"Limb Length Differences after Obstetrical Brachial Plexus Injury: A Growing Concern","volume":"130","author":"Bain","year":"2012","journal-title":"Plast. Reconstr. Surg."},{"key":"ref_59","unstructured":"Bubenik, G.A., and Bubenik, A.B. (2012). Horns, Pronghorns, and Antlers: Evolution, Morphology, Physiology, and Social Significance, Springer Science & Business Media."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"H759","DOI":"10.1152\/ajpheart.00842.2012","article-title":"Spontaneous Bursts of Muscle Sympathetic Nerve Activity Decrease Leg Vascular Conductance in Resting Humans","volume":"304","author":"Fairfax","year":"2013","journal-title":"Am. J. Physiol. Heart Circ. Physiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/0014-4886(76)90293-4","article-title":"In Vivo Limb Tissue Development in the Absence of Nerves: A Quantitative Study","volume":"53","author":"Popiela","year":"1976","journal-title":"Exp. Neurol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1086\/physzool.13.4.30151585","article-title":"The Primary Development of the Skeleton in Nerveless and Poorly Innervated Limb Transplants of Chick Embryos","volume":"13","author":"Hamburger","year":"1940","journal-title":"Physiol. Zool."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"639","DOI":"10.3109\/17453674.2010.504609","article-title":"Neuropeptide Y Innervation during Fracture Healing and Remodeling","volume":"81","author":"Long","year":"2010","journal-title":"Acta Orthop."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"553","DOI":"10.4161\/cam.4.4.12202","article-title":"Mechanism of Xenopus Cranial Neural Crest Cell Migration","volume":"4","author":"Alfandari","year":"2010","journal-title":"Cell Adhes. Migr."},{"key":"ref_65","unstructured":"Duband, J.-L. (2013). Neural Crest Delamination and Migration: Integrating Regulations of Cell Interactions, Locomotion, Survival and Fate. Madame Curie Bioscience Database [Internet], Landes Bioscience."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/0012-1606(87)90463-5","article-title":"Neural Crest Development in the Xenopus Laevis Embryo, Studied by Interspecific Transplantation and Scanning Electron Microscopy","volume":"124","author":"Sadaghiani","year":"1987","journal-title":"Dev. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"dev200356","DOI":"10.1242\/dev.200356","article-title":"Normal Table of Xenopus Development: A New Graphical Resource","volume":"149","author":"Zahn","year":"2022","journal-title":"Development"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1236","DOI":"10.1038\/nn.4088","article-title":"EAG2 Potassium Channel with Evolutionarily Conserved Function as a Brain Tumor Target","volume":"18","author":"Huang","year":"2015","journal-title":"Nat. Neurosci."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"754","DOI":"10.1002\/tox.23440","article-title":"Ivermectin Accelerates Autophagic Death of Glioma Cells by Inhibiting Glycolysis through Blocking GLUT4 Mediated JAK\/STAT Signaling Pathway Activation","volume":"37","author":"Feng","year":"2022","journal-title":"Environ. Toxicol."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Wang, X., Wang, J., Zhang, P., Zhang, C., Wang, W., Wu, M., Xu, W., Tao, L., Li, Z., and Zhang, Y. (2023). Cytotoxicity and Autophagy Induced by Ivermectin via AMPK\/mTOR Signaling Pathway in RAW264.7 Cells. Molecules, 28.","DOI":"10.3390\/molecules28052201"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1007\/s12032-025-02726-0","article-title":"Antitumor Potential of Ivermectin against T-Cell Lymphoma-Bearing Hosts","volume":"42","author":"Shukla","year":"2025","journal-title":"Med. Oncol."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Chu, C.-W., Ko, H.-J., Chou, C.-H., Cheng, T.-S., Cheng, H.-W., Liang, Y.-H., Lai, Y.-L., Lin, C.-Y., Wang, C., and Loh, J.-K. (2019). Thioridazine Enhances P62-Mediated Autophagy and Apoptosis Through Wnt\/\u03b2-Catenin Signaling Pathway in Glioma Cells. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20030473"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/S0022-3565(25)21626-3","article-title":"Effects of Thioridazine and Its Metabolites on Dopaminergic Function: Drug Metabolism as a Determinant of the Antidopaminergic Actions of Thioridazine","volume":"231","author":"Kilts","year":"1984","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/S0006-8993(97)00423-X","article-title":"Antipsychotic Drug Effects on Glutamatergic Activity","volume":"764","author":"Lidsky","year":"1997","journal-title":"Brain Res."},{"key":"ref_75","doi-asserted-by":"crossref","unstructured":"Picton, L.D., and Sillar, K.T. (2016). Mechanisms Underlying the Endogenous Dopaminergic Inhibition of Spinal Locomotor Circuit Function in Xenopus Tadpoles. Sci. Rep., 6.","DOI":"10.1038\/srep35749"},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Pio-Lopez, L., Kuchling, F., Tung, A., Pezzulo, G., and Levin, M. (2022). Active Inference, Morphogenesis, and Computational Psychiatry. Front. Comput. Neurosci., 16.","DOI":"10.3389\/fncom.2022.988977"},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Thammavongsa, D.A., Jackvony, T.N., Bookland, M.J., and Tang-Schomer, M.D. (2025). Targeting Ion Channels: Blockers Suppress Calcium Signals and Induce Cytotoxicity Across Medulloblastoma Cell Models. Bioengineering, 12.","DOI":"10.3390\/bioengineering12030268"},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Estrada-Mondragon, A., and Lynch, J.W. (2015). Functional Characterization of Ivermectin Binding Sites in \u03b11\u03b22\u03b32L GABA(A) Receptors. Front. Mol. Neurosci., 8.","DOI":"10.3389\/fnmol.2015.00055"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ibmb.2016.08.005","article-title":"Electrophysiological Characterization of Ivermectin Triple Actions on Musca Chloride Channels Gated by l-Glutamic Acid and \u03b3-Aminobutyric Acid","volume":"77","author":"Fuse","year":"2016","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/0014-2999(94)90500-2","article-title":"Effect of Ivermectin on Gamma-Aminobutyric Acid-Induced Chloride Currents in Mouse Hippocampal Embryonic Neurones","volume":"259","year":"1994","journal-title":"Eur. J. Pharmacol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"591","DOI":"10.1292\/jvms.10-0424","article-title":"Central and Peripheral Neurotoxic Effects of Ivermectin in Rats","volume":"73","author":"Trailovic","year":"2011","journal-title":"J. Vet. Med. Sci."},{"key":"ref_82","doi-asserted-by":"crossref","unstructured":"Jones, E., and McLaughlin, K.A. (2023). A Novel Perspective on Neuronal Control of Anatomical Patterning, Remodeling, and Maintenance. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241713358"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1007\/s00018-013-1549-0","article-title":"Roles of Innervation in Developing and Regenerating Orofacial Tissues","volume":"71","author":"Pagella","year":"2014","journal-title":"Cell Mol. Life Sci."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"e23282","DOI":"10.1002\/dvg.23282","article-title":"The Emerging Role of Cranial Nerves in Shaping Craniofacial Development","volume":"57","author":"Sudiwala","year":"2019","journal-title":"Genesis"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/0300-9629(76)90148-1","article-title":"Chemoreceptors of the Lateral-Line Organs in Intact, Hypophysectomized, and Prolactin-Treated Hypophysectomized Xenopus Laevis Specimens","volume":"55","author":"Blanchi","year":"1976","journal-title":"Comp. Biochem. Physiol. Part A Physiol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"108435","DOI":"10.1016\/j.pharmthera.2023.108435","article-title":"Prolactin and Pain of Endometriosis","volume":"247","author":"Lee","year":"2023","journal-title":"Pharmacol. Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1111\/j.1460-9568.2011.07788.x","article-title":"Endogenous Prolactin Generated during Peripheral Inflammation Contributes to Thermal Hyperalgesia","volume":"34","author":"Scotland","year":"2011","journal-title":"Eur. J. Neurosci."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/cpt197517173","article-title":"Thioridazine: Central Dopamine Turnover and Clinical Effects of Antipsychotic Drugs","volume":"17","author":"Bowers","year":"1975","journal-title":"Clin. Pharmacol. Ther."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1007\/s00213-003-1418-x","article-title":"Effect of Loxapine on Dopamine and Acetylcholine Release","volume":"167","author":"Li","year":"2003","journal-title":"Psychopharmacology"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.rvsc.2019.03.009","article-title":"Therapeutical Doses of Ivermectin and Its Association with Stress Disrupt Motor and Social Behaviors of Juvenile Rats and Serotonergic and Dopaminergic Systems","volume":"124","author":"Parisi","year":"2019","journal-title":"Res. Vet. Sci."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Wadsworth, H.A., Warnecke, A.M.P., Barlow, J.C., Robinson, J.K., Steimle, E., Ronstr\u00f6m, J.W., Williams, P.E., Galbraith, C.J., Baldridge, J., and Jakowec, M.W. (2024). Ivermectin Increases Striatal Cholinergic Activity to Facilitate Dopamine Terminal Function. Cell Biosci., 14.","DOI":"10.1186\/s13578-024-01228-2"}],"container-title":["Journal of Developmental Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2221-3759\/13\/3\/26\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:15:55Z","timestamp":1760033755000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2221-3759\/13\/3\/26"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,25]]},"references-count":91,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,9]]}},"alternative-id":["jdb13030026"],"URL":"https:\/\/doi.org\/10.3390\/jdb13030026","relation":{},"ISSN":["2221-3759"],"issn-type":[{"value":"2221-3759","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,25]]}}}