{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:27:05Z","timestamp":1786408025334,"version":"build-2736575974"},"reference-count":88,"publisher":"The Company of Biologists","issue":"19","license":[{"start":{"date-parts":[[2021,10,1]],"date-time":"2021-10-01T00:00:00Z","timestamp":1633046400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-1\/"}],"funder":[{"DOI":"10.13039\/100017305","name":"Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017305","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["DA045971"],"award-info":[{"award-number":["DA045971"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute on Drug Abuse","doi-asserted-by":"crossref","award":["DA030359"],"award-info":[{"award-number":["DA030359"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Tisch Cancer Institute at Mount Sinai","award":["P30 CA196521"],"award-info":[{"award-number":["P30 CA196521"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,10,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Many developmental disorders are thought to arise from an interaction between genetic and environmental risk factors. The Hedgehog (HH) signaling pathway regulates myriad developmental processes, and pathway inhibition is associated with birth defects, including holoprosencephaly (HPE). Cannabinoids are HH pathway inhibitors, but little is known of their effects on HH-dependent processes in mammalian embryos, and their mechanism of action is unclear. We report that the psychoactive cannabinoid \u03949-tetrahydrocannabinol (THC) induces two hallmark HH loss-of-function phenotypes (HPE and ventral neural tube patterning defects) in Cdon mutant mice, which have a subthreshold deficit in HH signaling. THC therefore acts as a \u2018conditional teratogen\u2019, dependent on a complementary but insufficient genetic insult. In vitro findings indicate that THC is a direct inhibitor of the essential HH signal transducer smoothened. The canonical THC receptor, cannabinoid receptor-type 1, is not required for THC to inhibit HH signaling. Cannabis consumption during pregnancy may contribute to a combination of risk factors underlying specific developmental disorders. These findings therefore have significant public health relevance.<\/jats:p>","DOI":"10.1242\/dev.199585","type":"journal-article","created":{"date-parts":[[2021,10,5]],"date-time":"2021-10-05T17:57:57Z","timestamp":1633456677000},"source":"Crossref","is-referenced-by-count":14,"title":["\u03949-Tetrahydrocannabinol inhibits Hedgehog-dependent patterning during development"],"prefix":"10.1242","volume":"148","author":[{"given":"Hsiao-Fan","family":"Lo","sequence":"first","affiliation":[{"name":"Department of Cell, Developmental, and Regenerative Biology, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingi","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Regenerative Biology, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrietta","family":"Szutorisz","sequence":"additional","affiliation":[{"name":"Addiction Institute and Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasmin L.","family":"Hurd","sequence":"additional","affiliation":[{"name":"Addiction Institute and Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7661-3335","authenticated-orcid":false,"given":"Robert S.","family":"Krauss","sequence":"additional","affiliation":[{"name":"Department of Cell, Developmental, and Regenerative Biology, New York, NY 10029, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2021,10,5]]},"reference":[{"key":"2021101115590647000_DEV199585C1","doi-asserted-by":"publisher","first-page":"775","DOI":"10.1016\/j.devcel.2011.04.018","article-title":"Overlapping roles and collective requirement for the co-receptors GAS1, CDO and BOC in SHH pathway function","volume":"20","author":"Allen","year":"2011","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C2","doi-asserted-by":"publisher","first-page":"D1038","DOI":"10.1093\/nar\/gky1151","article-title":"OMIM.org: leveraging knowledge across phenotype-gene relationships","volume":"47","author":"Amberger","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2021101115590647000_DEV199585C3","doi-asserted-by":"publisher","first-page":"a028175","DOI":"10.1101\/cshperspect.a028175","article-title":"Primary cilia and mammalian Hedgehog signaling","volume":"9","author":"Bangs","year":"2017","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2021101115590647000_DEV199585C4","doi-asserted-by":"publisher","DOI":"10.1242\/dev.191064","article-title":"Gene-environment interactions: aligning birth defects research with complex etiology","volume":"147","author":"Beames","year":"2020","journal-title":"Development"},{"key":"2021101115590647000_DEV199585C5","doi-asserted-by":"publisher","first-page":"e0230167","DOI":"10.1371\/journal.pone.0230167","article-title":"Mapping cannabis potency in medical and recreational programs in the United States","volume":"15","author":"Cash","year":"2020","journal-title":"PLoS One"},{"key":"2021101115590647000_DEV199585C6","doi-asserted-by":"publisher","first-page":"2743","DOI":"10.1101\/gad.1025302","article-title":"Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened","volume":"16","author":"Chen","year":"2002","journal-title":"Genes & Dev"},{"key":"2021101115590647000_DEV199585C7","article-title":"Global report on birth defects","volume-title":"March of Dimes Global Report on Birth Defects: The hidden toll of dying and disabled children","author":"Christianson","year":"2006"},{"key":"2021101115590647000_DEV199585C8","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1002\/bdra.20295","article-title":"Holoprosencephaly: clinical, anatomic, and molecular dimensions","volume":"76","author":"Cohen","year":"2006","journal-title":"Birth Defects Res Part A Clin Mol Teratol"},{"key":"2021101115590647000_DEV199585C9","doi-asserted-by":"publisher","first-page":"411","DOI":"10.1016\/S0960-9822(03)00088-5","article-title":"Microform holoprosencephaly in mice that lack the Ig superfamily member Cdon","volume":"13","author":"Cole","year":"2003","journal-title":"Curr. Biol."},{"key":"2021101115590647000_DEV199585C10","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1002\/(SICI)1096-8628(20000214)90:4<320::AID-AJMG11>3.0.CO;2-8","article-title":"Risk factors for cytogenetically normal holoprosencephaly in California: a population-based case-control study","volume":"90","author":"Croen","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"2021101115590647000_DEV199585C11","doi-asserted-by":"publisher","first-page":"2489","DOI":"10.1242\/dev.009324","article-title":"Pattern formation in the vertebrate neural tube: a sonic hedgehog morphogen-regulated transcriptional network","volume":"135","author":"Dessaud","year":"2008","journal-title":"Development"},{"key":"2021101115590647000_DEV199585C12","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/978-1-61779-458-2_14","article-title":"Rat Models of Prenatal and Adolescent Cannabis Exposure","volume-title":"Psychiatric Disorders Methods in Molecular Biology","author":"DiNieri","year":"2012"},{"key":"2021101115590647000_DEV199585C13","doi-asserted-by":"crossref","first-page":"2023","DOI":"10.1089\/ars.2007.2019","article-title":"Nrf2-Mediated Transcriptional Induction of Antioxidant Response in Mouse Embryos Exposed to Ethanol in vivo: Implications for the Prevention of Fetal Alcohol Spectrum Disorders","volume":"10","author":"Dong","year":"2008","journal-title":"Antioxid Redox Signal."},{"key":"2021101115590647000_DEV199585C14","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1007\/978-3-030-57369-0_3","article-title":"Neuropharmacological Effects of the Main Phytocannabinoids: a narrative review","volume":"1264","author":"Dos Santos","year":"2021","journal-title":"Adv. Exp. Med. Biol."},{"key":"2021101115590647000_DEV199585C15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.ydbio.2010.07.008","article-title":"O-fucosylation of thrombospondin type 1 repeats restricts epithelial to mesenchymal transition (EMT) and maintains epiblast pluripotency during mouse gastrulation","volume":"346","author":"Du","year":"2010","journal-title":"Dev. Biol."},{"key":"2021101115590647000_DEV199585C16","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1002\/ajmg.c.31619","article-title":"Recent advances in understanding inheritance of holoprosencephaly","volume":"178","author":"Dubourg","year":"2018","journal-title":"Am. J. Med. Genet."},{"key":"2021101115590647000_DEV199585C17","doi-asserted-by":"publisher","first-page":"8463","DOI":"10.1128\/JVI.72.11.8463-8471.1998","article-title":"A third-generation lentivirus vector with a conditional packaging system","volume":"72","author":"Dull","year":"1998","journal-title":"J. Virol."},{"key":"2021101115590647000_DEV199585C18","doi-asserted-by":"publisher","first-page":"108680","DOI":"10.1016\/j.jneumeth.2020.108680","article-title":"Revisiting CB1 cannabinoid receptor detection and the exploration of its interacting partners","volume":"337","author":"Esteban","year":"2020","journal-title":"J. Neurosci. Methods"},{"key":"2021101115590647000_DEV199585C19","doi-asserted-by":"publisher","first-page":"16057","DOI":"10.1038\/s41598-019-52336-w","article-title":"Cannabinoids exacerbate alcohol teratogenesis by a CB1-Hedgehog interaction","volume":"9","author":"Fish","year":"2019","journal-title":"Sci. Rep."},{"key":"2021101115590647000_DEV199585C20","first-page":"796","article-title":"The William Allan Memorial Award Address: evolution of a palatable multifactorial threshold model","volume":"32","author":"Fraser","year":"1980","journal-title":"Am. J. Hum. Genet."},{"key":"2021101115590647000_DEV199585C21","doi-asserted-by":"publisher","first-page":"e377","DOI":"10.1002\/wdev.377","article-title":"Signaling in the primary cilium through the lens of the Hedgehog pathway","volume":"9","author":"Gigante","year":"2020","journal-title":"WIREs Dev Biol"},{"key":"2021101115590647000_DEV199585C22","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.ntt.2015.12.004","article-title":"Dose-dependent teratogenicity of the synthetic cannabinoid CP-55,940 in mice","volume":"58","author":"Gilbert","year":"2015","journal-title":"Neurotoxicol. Teratol."},{"key":"2021101115590647000_DEV199585C23","first-page":"99","article-title":"Teratogenic causes of malformations","volume":"40","author":"Gilbert-Barness","year":"2010","journal-title":"Ann. Clin. Lab. Sci."},{"key":"2021101115590647000_DEV199585C24","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1126\/science.277.5329.1109","article-title":"Altered neural cell fates and medulloblastoma in mouse patched mutants","volume":"277","author":"Goodrich","year":"1997","journal-title":"Science"},{"key":"2021101115590647000_DEV199585C25","doi-asserted-by":"publisher","first-page":"29085","DOI":"10.1074\/jbc.M602516200","article-title":"Induction of Krox-24 by endogenous cannabinoid type 1 receptors in Neuro2A cells is mediated by the MEK-ERK MAPK pathway and is suppressed by the phosphatidylinositol 3-kinase pathway","volume":"281","author":"Graham","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021101115590647000_DEV199585C26","doi-asserted-by":"publisher","first-page":"327","DOI":"10.2165\/00003088-200342040-00003","article-title":"Pharmacokinetics and pharmacodynamics of cannabinoids","volume":"42","author":"Grotenhermen","year":"2003","journal-title":"Clin. Pharmacokinet."},{"key":"2021101115590647000_DEV199585C27","doi-asserted-by":"publisher","first-page":"e009986","DOI":"10.1136\/bmjopen-2015-009986","article-title":"Prenatal exposure to cannabis and maternal and child health outcomes: a systematic review and meta-analysis","volume":"6","author":"Gunn","year":"2016","journal-title":"BMJ Open"},{"key":"2021101115590647000_DEV199585C28","doi-asserted-by":"publisher","first-page":"33426","DOI":"10.1074\/jbc.M502812200","article-title":"The G alpha(o\/i)-coupled cannabinoid receptor-mediated neurite outgrowth involves Rap regulation of Src and Stat3","volume":"280","author":"He","year":"2005","journal-title":"J. Biol. Chem."},{"key":"2021101115590647000_DEV199585C29","doi-asserted-by":"crossref","first-page":"e0120517","DOI":"10.1371\/journal.pone.0120517","article-title":"Definition of critical periods for hedgehog pathway antagonist-induced holoprosencephaly, cleft lip, and cleft palate","volume":"10","author":"Heyne","year":"2015","journal-title":"PLoS One"},{"key":"2021101115590647000_DEV199585C30","doi-asserted-by":"crossref","first-page":"e1002999","DOI":"10.1371\/journal.pgen.1002999","article-title":"Cdon mutation and fetal ethanol exposure synergize to produce midline signaling defects and holoprosencephaly spectrum disorders in mice","volume":"8","author":"Hong","year":"2012","journal-title":"PLoS Genet."},{"key":"2021101115590647000_DEV199585C31","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1002\/ajmg.c.31611","article-title":"Modeling the complex etiology of holoprosencephaly in mice","volume":"178C","author":"Hong","year":"2018","journal-title":"Am J of Med Genet"},{"key":"2021101115590647000_DEV199585C32","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1016\/j.cell.2016.08.003","article-title":"Cellular cholesterol directly activates smoothened in Hedgehog signaling","volume":"166","author":"Huang","year":"2016","journal-title":"Cell"},{"key":"2021101115590647000_DEV199585C33","doi-asserted-by":"publisher","first-page":"312","DOI":"10.1016\/j.cell.2018.04.029","article-title":"Structural basis of smoothened activation in Hedgehog signaling","volume":"174","author":"Huang","year":"2018","journal-title":"Cell"},{"key":"2021101115590647000_DEV199585C34","doi-asserted-by":"publisher","first-page":"788","DOI":"10.1016\/j.devcel.2011.04.017","article-title":"Boc and Gas1 each form distinct Shh receptor complexes with Ptch1 and are required for Shh-mediated cell proliferation","volume":"20","author":"Izzi","year":"2011","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C35","doi-asserted-by":"publisher","first-page":"3415","DOI":"10.1073\/pnas.1416463112","article-title":"Endocannabinoids are conserved inhibitors of the Hedgehog pathway","volume":"112","author":"Khaliullina","year":"2015","journal-title":"Proc Natl Acad Sci. USA"},{"key":"2021101115590647000_DEV199585C36","doi-asserted-by":"publisher","first-page":"dev166892","DOI":"10.1242\/dev.166892","article-title":"Biochemical mechanisms of vertebrate hedgehog signaling","volume":"146","author":"Kong","year":"2019","journal-title":"Development"},{"key":"2021101115590647000_DEV199585C37","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1016\/j.sbi.2019.05.015","article-title":"Structures of vertebrate Patched and Smoothened reveal intimate links between cholesterol and Hedgehog signalling","volume":"57","author":"Kowatsch","year":"2019","journal-title":"Curr. Opin. Struct. Biol."},{"key":"2021101115590647000_DEV199585C38","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1017\/S1462399407000440","article-title":"Holoprosencephaly: new models, new insights","volume":"9","author":"Krauss","year":"2007","journal-title":"Expert Rev. Mol. Med."},{"key":"2021101115590647000_DEV199585C39","doi-asserted-by":"publisher","first-page":"569","DOI":"10.1016\/bs.ctdb.2015.12.010","article-title":"Gene\u2013environment Interactions and the etiology of birth defects","volume":"116","author":"Krauss","year":"2016","journal-title":"Curr. Top. Dev. Biol."},{"key":"2021101115590647000_DEV199585C40","doi-asserted-by":"publisher","first-page":"367","DOI":"10.1242\/dev.120154","article-title":"Hedgehog signalling","volume":"143","author":"Lee","year":"2016","journal-title":"Development"},{"key":"2021101115590647000_DEV199585C41","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1002\/bdra.20479","article-title":"Frequency of holoprosencephaly in the International Clearinghouse Birth Defects Surveillance Systems: searching for population variations","volume":"82","author":"Leoncini","year":"2008","journal-title":"Birth Defects Res. A Clin. Mol. Teratol"},{"key":"2021101115590647000_DEV199585C42","doi-asserted-by":"publisher","first-page":"1161","DOI":"10.2105\/AJPH.73.10.1161","article-title":"The association of marijuana use with outcome of pregnancy","volume":"73","author":"Linn","year":"1983","journal-title":"Am. J. Public Health"},{"key":"2021101115590647000_DEV199585C43","doi-asserted-by":"publisher","first-page":"e247","DOI":"10.1002\/wdev.247","article-title":"Gene\u2013environment interactions in development and disease","volume":"6","author":"Lovely","year":"2017","journal-title":"WIREs Dev Biol"},{"key":"2021101115590647000_DEV199585C44","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1016\/j.bpsc.2020.07.016","article-title":"Review of the Endocannabinoid System","volume":"6","author":"Lu","year":"2020","journal-title":"Biol Psychiatry Cogn Neurosci Neuroimaging"},{"key":"2021101115590647000_DEV199585C45","doi-asserted-by":"publisher","first-page":"2976","DOI":"10.1523\/JNEUROSCI.4465-07.2008","article-title":"Downregulation of the CB1 cannabinoid receptor and related molecular elements of the endocannabinoid system in epileptic human hippocampus","volume":"28","author":"Lud\u00e1nyi","year":"2008","journal-title":"J. Neurosci."},{"key":"2021101115590647000_DEV199585C46","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.tips.2015.02.008","article-title":"Endocannabinoid signaling at the periphery: 50 years after THC","volume":"36","author":"Maccarrone","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"2021101115590647000_DEV199585C47","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1002\/ajmg.c.30244","article-title":"Risk factors for non-syndromic holoprosencephaly in the National Birth Defects Prevention Study","volume":"154C","author":"Miller","year":"2010","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021101115590647000_DEV199585C48","first-page":"6203","article-title":"Holoprosencephaly","volume-title":"The Metabolic & Molecular Bases of Inherited Disease","author":"Muenke","year":"2001"},{"key":"2021101115590647000_DEV199585C49","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1016\/j.cell.2012.12.026","article-title":"The ciliary G-Protein-coupled receptor Gpr161 negatively regulates the sonic Hedgehog pathway via cAMP signaling","volume":"152","author":"Mukhopadhyay","year":"2013","journal-title":"Cell"},{"key":"2021101115590647000_DEV199585C50","doi-asserted-by":"crossref","first-page":"8760","DOI":"10.1073\/pnas.0803545105","article-title":"Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning","volume":"105","author":"Mulder","year":"2008","journal-title":"Proc Natl Acad Sci"},{"key":"2021101115590647000_DEV199585C51","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1111\/j.1399-0004.2004.00360.x","article-title":"Hedgehog signaling and congenital malformations","volume":"67","author":"Nieuwenhuis","year":"2005","journal-title":"Clin. Genet."},{"key":"2021101115590647000_DEV199585C52","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1002\/hep.23525","article-title":"Hedgehog signaling is critical for normal liver regeneration after partial hepatectomy in mice","volume":"51","author":"Ochoa","year":"2010","journal-title":"Hepatology"},{"key":"2021101115590647000_DEV199585C53","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1146\/annurev-cellbio-100616-060847","article-title":"Sending and receiving Hedgehog signals","volume":"33","author":"Petrov","year":"2017","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"2021101115590647000_DEV199585C54","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1002\/wdev.161","article-title":"Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans","volume":"4","author":"Petryk","year":"2015","journal-title":"Wiley Interdiscip Rev Dev Biol"},{"key":"2021101115590647000_DEV199585C55","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1002\/bdrb.20348","article-title":"Cannabinoid receptor 1 signaling in embryo neurodevelopment","volume":"95","author":"Psychoyos","year":"2012","journal-title":"Birth Defects Res. B Dev. Reprod. Toxicol."},{"key":"2021101115590647000_DEV199585C56","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.tibs.2020.01.006","article-title":"Mechanistic insights into the generation and transduction of Hedgehog signaling","volume":"45","author":"Qi","year":"2020","journal-title":"Trends Biochem. Sci."},{"key":"2021101115590647000_DEV199585C57","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1038\/s41589-020-00678-2","article-title":"Cholesterol access in cellular membranes controls Hedgehog signaling","volume":"16","author":"Radhakrishnan","year":"2020","journal-title":"Nat. Chem. Biol."},{"key":"2021101115590647000_DEV199585C58","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1177\/0009922819861281","article-title":"Cannabis teratology explains current patterns of Coloradan congenital defects: the contribution of increased Cannabinoid exposure to rising teratological trends","volume":"58","author":"Reece","year":"2019","journal-title":"Clinical Pediatrics"},{"key":"2021101115590647000_DEV199585C59","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1186\/s12887-020-02431-z","article-title":"Contemporary epidemiology of rising atrial septal defect trends across USA 1991\u20132016: a combined ecological geospatiotemporal and causal inferential study","volume":"20","author":"Reece","year":"2020","journal-title":"BMC Pediatr."},{"key":"2021101115590647000_DEV199585C60","doi-asserted-by":"publisher","first-page":"1505","DOI":"10.1038\/nm.3314","article-title":"Activation of Hedgehog signaling by loss of GNAS causes heterotopic ossification","volume":"19","author":"Regard","year":"2013","journal-title":"Nat. Med."},{"key":"2021101115590647000_DEV199585C61","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1101\/gad.559910","article-title":"Distinct Sonic Hedgehog signaling dynamics specify floor plate and ventral neuronal progenitors in the vertebrate neural tube","volume":"24","author":"Ribes","year":"2010","journal-title":"Genes Dev."},{"key":"2021101115590647000_DEV199585C62","doi-asserted-by":"publisher","first-page":"658","DOI":"10.1016\/j.ymgme.2012.01.005","article-title":"Utilizing prospective sequence analysis of SHH, ZIC2, SIX3 and TGIF in holoprosencephaly probands to describe the parameters limiting the observed frequency of mutant gene\u00d7gene interactions","volume":"105","author":"Roessler","year":"2012","journal-title":"Mol. Genet. Metab."},{"key":"2021101115590647000_DEV199585C63","doi-asserted-by":"publisher","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 Part C"},{"key":"2021101115590647000_DEV199585C64","doi-asserted-by":"crossref","first-page":"3196","DOI":"10.1073\/pnas.0813373106","article-title":"Hedgehog signal transduction by Smoothened: Pharmacologic evidence for a 2-step activation process","volume":"106","author":"Rohatgi","year":"2009","journal-title":"Proc Natl Acad Sci"},{"key":"2021101115590647000_DEV199585C65","doi-asserted-by":"publisher","first-page":"e162","DOI":"10.1111\/epi.13930","article-title":"Cannabinoid receptor 1\/2 double-knockout mice develop epilepsy","volume":"58","author":"Rowley","year":"2017","journal-title":"Epilepsia"},{"key":"2021101115590647000_DEV199585C66","doi-asserted-by":"publisher","first-page":"dev182154","DOI":"10.1242\/dev.182154","article-title":"Establishing neuronal diversity in the spinal cord: a time and a place","volume":"146","author":"Sagner","year":"2019","journal-title":"Development"},{"key":"2021101115590647000_DEV199585C67","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1007\/164_2019_298","article-title":"Molecular mechanism and Cannabinoid pharmacology","volume":"258","author":"Schurman","year":"2020","journal-title":"Handb. Exp. Pharmacol."},{"key":"2021101115590647000_DEV199585C68","doi-asserted-by":"publisher","first-page":"5904","DOI":"10.1073\/pnas.1604984113","article-title":"Endogenous B-ring oxysterols inhibit the Hedgehog component Smoothened in a manner distinct from cyclopamine or side-chain oxysterols","volume":"113","author":"Sever","year":"2016","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"2021101115590647000_DEV199585C69","doi-asserted-by":"publisher","first-page":"246","DOI":"10.1038\/nchembio.1776","article-title":"Regulation of the oncoprotein Smoothened by small molecules","volume":"11","author":"Sharpe","year":"2015","journal-title":"Nat. Chem. Biol."},{"key":"2021101115590647000_DEV199585C70","doi-asserted-by":"publisher","first-page":"623","DOI":"10.1002\/bdr2.1888","article-title":"A life-table analysis of the intrauterine fate of malformed human embryos and fetuses","volume":"113","author":"Shiota","year":"2021","journal-title":"Birth Defects Res"},{"key":"2021101115590647000_DEV199585C71","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1002\/ajmg.c.30248","article-title":"Early pathogenesis of holoprosencephaly","volume":"154C","author":"Shiota","year":"2010","journal-title":"Am. J. Med. Genet. C Semin. Med. Genet."},{"key":"2021101115590647000_DEV199585C72","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.devcel.2020.06.034","article-title":"Ankmy2 prevents smoothened-independent hyperactivation of the Hedgehog pathway via cilia-regulated adenylyl cyclase signaling","volume":"54","author":"Somatilaka","year":"2020","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C73","doi-asserted-by":"publisher","first-page":"1051","DOI":"10.1111\/acel.12638","article-title":"Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition","volume":"16","author":"Sophocleous","year":"2017","journal-title":"Aging Cell"},{"key":"2021101115590647000_DEV199585C74","doi-asserted-by":"publisher","first-page":"187","DOI":"10.1016\/j.devcel.2005.12.013","article-title":"Genetic elimination of suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway","volume":"10","author":"Svard","year":"2006","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C75","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1038\/35023008","article-title":"Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine","volume":"406","author":"Taipale","year":"2000","journal-title":"Nature"},{"key":"2021101115590647000_DEV199585C76","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1016\/j.devcel.2006.04.004","article-title":"The cell surface membrane proteins Cdo and Boc are components and targets of the hedgehog signaling pathway and feedback network in mice","volume":"10","author":"Tenzen","year":"2006","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C77","doi-asserted-by":"publisher","first-page":"14","DOI":"10.3389\/fcell.2017.00014","article-title":"Sonic Hedgehog Signaling in limb development","volume":"5","author":"Tickle","year":"2017","journal-title":"Front Cell Dev Biol"},{"key":"2021101115590647000_DEV199585C78","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1097\/EDE.0b013e31818e5930","article-title":"Maternal periconceptional illicit drug use and the risk of congenital malformations","volume":"20","author":"van Gelder","year":"2009","journal-title":"Epidemiology"},{"key":"2021101115590647000_DEV199585C79","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.drugalcdep.2010.01.007","article-title":"Characteristics of pregnant illicit drug users and associations between cannabis use and perinatal outcome in a population-based study","volume":"109","author":"van Gelder","year":"2010","journal-title":"Drug and Alcohol Depend"},{"key":"2021101115590647000_DEV199585C80","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1001\/jama.2016.18612","article-title":"The risks of Marijuana use during pregnancy","volume":"317","author":"Volkow","year":"2017","journal-title":"JAMA"},{"key":"2021101115590647000_DEV199585C81","doi-asserted-by":"publisher","first-page":"132","DOI":"10.1016\/j.devcel.2019.07.006","article-title":"We are all developmental biologists","volume":"50","author":"Wallingford","year":"2019","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C82","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/j.mcn.2008.02.001","article-title":"The endocannabinoid receptor, CB1, is required for normal axonal growth and fasciculation","volume":"38","author":"Watson","year":"2008","journal-title":"Mol Cellular Neurosci"},{"key":"2021101115590647000_DEV199585C83","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1002\/bdra.23385","article-title":"Developments in our understanding of the genetic basis of birth defects","volume":"103","author":"Webber","year":"2015","journal-title":"Birth Defects Research Part A: Clinical and Molecular Teratology"},{"key":"2021101115590647000_DEV199585C84","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.devcel.2020.09.017","article-title":"Hedgehog pathway activation requires coreceptor-catalyzed, lipid-dependent relay of the Sonic Hedgehog ligand","volume":"55","author":"Wierbowski","year":"2020","journal-title":"Dev. Cell"},{"key":"2021101115590647000_DEV199585C85","doi-asserted-by":"publisher","first-page":"e5182","DOI":"10.1371\/journal.pone.0005182","article-title":"Smoothened adopts multiple active and inactive conformations capable of trafficking to the primary cilium","volume":"4","author":"Wilson","year":"2009","journal-title":"PLoS One"},{"key":"2021101115590647000_DEV199585C86","doi-asserted-by":"publisher","first-page":"2490","DOI":"10.1001\/jama.2017.17225","article-title":"Trends in self-reported and biochemically tested Marijuana use among pregnant females in California from 2009-2016","volume":"318","author":"Young-Wolff","year":"2017","journal-title":"JAMA"},{"key":"2021101115590647000_DEV199585C87","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1242\/dev.02720","article-title":"GATA and Nkx factors synergistically regulate tissue-specific gene expression and development in vivo","volume":"134","author":"Zhang","year":"2007","journal-title":"Development"},{"key":"2021101115590647000_DEV199585C88","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1242\/dmm.005744","article-title":"Boc modifies the holoprosencephaly spectrum of Cdo mutant mice","volume":"4","author":"Zhang","year":"2011","journal-title":"Dis Model Mech"}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.199585\/2108232\/dev199585.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.199585\/2108232\/dev199585.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,10,11]],"date-time":"2021-10-11T12:00:53Z","timestamp":1633953653000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/148\/19\/dev199585\/272342\/9-Tetrahydrocannabinol-inhibits-Hedgehog-dependent"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,1]]},"references-count":88,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2021,10,1]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.199585","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2021.01.18.427140","asserted-by":"object"}]},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,1]]},"article-number":"dev199585"}}