{"doi":"10.1101/2025.04.23.650288","title":"Interactions between the Bone Morphogenetic Protein and the Planar Cell Polarity Pathways lead to distinctive ethanol-induced facial defects","abstract":"Abstract Background Fetal Alcohol Spectrum Disorders (FASD) describes a spectrum of ethanol-induced neural and facial developmental defects. Ethanol susceptibility is modulated by genetics, but their underlying mechanisms remain poorly understood. In all vertebrates, a series of complex cellular events give rise to the body plan, including convergence & extension (C&E) and endoderm/ cranial neural crest (CNC-which gives rise to the facial skeleton) morphogenesis. These events are critical to establish complex signaling interactions, driving embryo development, including the facial skeleton. In zebrafish, C&E occurs between 6-10 hpf while endoderm/CNC morphogenesis occurs 10-24 hpf. Previous work shows that the PCP mutants are sensitive to ethanol from 6-24 hpf, covering both C&E and endoderm/CNC morphogenesis and exhibiting multiple defects to the forming head raising the question whether ethanol during both time windows drives PCP-ethanol defects. We hypothesize that PCP single and double mutants are ethanol sensitive 10-24 hpf, after C&E. We also hypothesize BMP signaling (sensitive 10-18 hpf) interacts with and sensitizes the PCP pathway to ethanol. Methods Here, we treated PCP/BMP mutants with ethanol from 6-10, 10-18, 10-24 or 24-30 hpf and combined morphometric and linear measurements to examine facial development. Results We show that PCP mutant larvae are ethanol-sensitive from 10-24 hpf, but not 6-10 or 24-30 hpf. We also show that BMP mutants sensitize PCP mutants to ethanol and lead to novel ethanol-independent midline craniofacial defects. Our results suggest that the ethanol-sensitive role of PCP pathway occurs after C&E, during endoderm/CNC morphogenesis and that the PCP and BMP pathways genetically interact during the morphogenesis events. Conclusions Ultimately, our work builds on a mechanistic paradigm of ethanol-induced birth defects we have been developing, connecting conceptual framework with concrete cellular events that could be ethanol-sensitive beyond facial development.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":564907,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9439,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1468509,"name":"Anna Llyod","orcid":null,"position":1,"is_corresponding":false},{"id":705205,"name":"C. Ben Lovely","orcid":"0000-0002-7838-5823","position":2,"is_corresponding":false},{"id":1169320,"name":"Raèden Gray","orcid":"0000-0001-7792-8358","position":0,"is_corresponding":true}],"reference_count":66,"raw_metadata":null,"created_at":"2026-07-19T02:56:24.872312Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}