{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T19:56:44Z","timestamp":1760385404612,"version":"3.41.2"},"reference-count":48,"publisher":"The Company of Biologists","license":[{"start":{"date-parts":[[2021,5,18]],"date-time":"2021-05-18T00:00:00Z","timestamp":1621296000000},"content-version":"am","delay-in-days":2329,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS.<\/jats:p>","DOI":"10.1242\/dmm.017889","type":"journal-article","created":{"date-parts":[[2014,12,25]],"date-time":"2014-12-25T05:26:43Z","timestamp":1419485203000},"source":"Crossref","is-referenced-by-count":11,"title":["Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology"],"prefix":"10.1242","author":[{"given":"Nandini","family":"Singh","sequence":"first","affiliation":[{"name":"Department of Anthropology, Pennsylvania State University, University Park, PA, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tara","family":"Dutka","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Institute of Genetic Medicine, Baltimore, MD, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benjamin M.","family":"Devenney","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Department of Physiology, Baltimore, MD, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuhiko","family":"Kawasaki","sequence":"additional","affiliation":[{"name":"Department of Anthropology, Pennsylvania State University, University Park, PA, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger H.","family":"Reeves","sequence":"additional","affiliation":[{"name":"Johns Hopkins University School of Medicine, Institute of Genetic Medicine, Baltimore, MD, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joan T.","family":"Richtsmeier","sequence":"additional","affiliation":[{"name":"Department of Anthropology, Pennsylvania State University, University Park, PA, USA;"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2015,1,1]]},"reference":[{"key":"2021042501194737800_b1-0080271","doi-asserted-by":"crossref","first-page":"1304","DOI":"10.1016\/S0960-9822(00)80052-4","article-title":"Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death","volume":"9","author":"Ahlgren","year":"1999","journal-title":"Curr. Biol."},{"key":"2021042501194737800_b2-0080271","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/hmg\/9.2.195","article-title":"Discovery and genetic localization of Down syndrome cerebellar phenotypes using the Ts65Dn mouse","volume":"9","author":"Baxter","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"2021042501194737800_b3-0080271","doi-asserted-by":"crossref","first-page":"14071","DOI":"10.1073\/pnas.182542899","article-title":"Small molecule modulation of Smoothened activity","volume":"99","author":"Chen","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501194737800_b4-0080271","doi-asserted-by":"crossref","first-page":"2257","DOI":"10.1126\/science.1104135","article-title":"Activity-dependent internalization of smoothened mediated by \u03b2-arrestin 2 and GRK2","volume":"306","author":"Chen","year":"2004","journal-title":"Science"},{"key":"2021042501194737800_b5-0080271","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":"2021042501194737800_b6-0080271","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1002\/ajmg.a.20495","article-title":"The hedgehog signaling network","volume":"123A","author":"Cohen","year":"2003","journal-title":"Am. J. Med. Genet."},{"key":"2021042501194737800_b7-0080271","first-page":"44","article-title":"The role of sonic hedgehog signaling in craniofacial development","volume-title":"Shh and Gli Signaling and Development","author":"Cordero","year":"2006"},{"key":"2021042501194737800_b8-0080271","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/B978-0-444-54299-1.00011-X","article-title":"A Sonic hedgehog (Shh) response deficit in trisomic cells may be a common denominator for multiple features of Down syndrome","volume":"197","author":"Currier","year":"2012","journal-title":"Prog. Brain Res."},{"key":"2021042501194737800_b9-0080271","doi-asserted-by":"crossref","first-page":"3089","DOI":"10.1242\/dev.126.14.3089","article-title":"Sonic hedgehog regulates the growth and patterning of the cerebellum","volume":"126","author":"Dahmane","year":"1999","journal-title":"Development"},{"key":"2021042501194737800_b10-0080271","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1242\/dmm.007716","article-title":"The use of mouse models to understand and improve cognitive deficits in Down syndrome","volume":"4","author":"Das","year":"2011","journal-title":"Dis. Model. Mech."},{"key":"2021042501194737800_b11-0080271","doi-asserted-by":"crossref","first-page":"201ra120","DOI":"10.1126\/scitranslmed.3005983","article-title":"Hedgehog agonist therapy corrects structural and cognitive deficits in a Down syndrome mouse model","volume":"5","author":"Das","year":"2013","journal-title":"Sci. Transl. Med."},{"key":"2021042501194737800_b12-0080271","first-page":"117","article-title":"Segmental trisomy as a mouse model for Down syndrome","volume":"384","author":"Davisson","year":"1993","journal-title":"Prog. Clin. Biol. Res."},{"volume-title":"Statistical Shape Analysis","year":"1998","author":"Dryden","key":"2021042501194737800_b13-0080271"},{"key":"2021042501194737800_b14-0080271","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1016\/j.tins.2011.11.001","article-title":"Trisomy 21 and early brain development","volume":"35","author":"Haydar","year":"2012","journal-title":"Trends Neurosci."},{"key":"2021042501194737800_b15-0080271","doi-asserted-by":"crossref","first-page":"105ra104","DOI":"10.1126\/scitranslmed.3002731","article-title":"A small-molecule smoothened agonist prevents glucocorticoid-induced neonatal cerebellar injury","volume":"3","author":"Heine","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"2021042501194737800_b16-0080271","doi-asserted-by":"crossref","first-page":"4873","DOI":"10.1242\/dev.126.21.4873","article-title":"The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis","volume":"126","author":"Hu","year":"1999","journal-title":"Development"},{"key":"2021042501194737800_b17-0080271","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1242\/dev.026583","article-title":"A SHH-responsive signaling center in the forebrain regulates craniofacial morphogenesis via the facial ectoderm","volume":"136","author":"Hu","year":"2009","journal-title":"Development"},{"key":"2021042501194737800_b18-0080271","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.ydbio.2008.10.026","article-title":"Unique organization of the frontonasal ectodermal zone in birds and mammals","volume":"325","author":"Hu","year":"2009","journal-title":"Dev. Biol."},{"key":"2021042501194737800_b19-0080271","doi-asserted-by":"crossref","first-page":"1749","DOI":"10.1242\/dev.00397","article-title":"A zone of frontonasal ectoderm regulates patterning and growth in the face","volume":"130","author":"Hu","year":"2003","journal-title":"Development"},{"key":"2021042501194737800_b20-0080271","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nrg1969","article-title":"Orchestrating ontogenesis: variations on a theme by sonic hedgehog","volume":"7","author":"Ingham","year":"2006","journal-title":"Nat. Rev. Genet."},{"key":"2021042501194737800_b21-0080271","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1097\/01.sap.0000232833.41739.a5","article-title":"Expression of Indian Hedgehog, BMP-4 and Noggin in craniosynostosis induced by fetal constraint","volume":"58","author":"Jacob","year":"2007","journal-title":"Ann. Plast. Surg."},{"key":"2021042501194737800_b22-0080271","doi-asserted-by":"crossref","first-page":"937","DOI":"10.1101\/gad.1190304","article-title":"Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia","volume":"18","author":"Jeong","year":"2004","journal-title":"Genes Dev."},{"key":"2021042501194737800_b23-0080271","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1242\/dev.127.3.543","article-title":"Indian hedgehog coordinates endochondral bone growth and morphogenesis via parathyroid hormone related-protein-dependent and -independent pathways","volume":"127","author":"Karp","year":"2000","journal-title":"Development"},{"key":"2021042501194737800_b24-0080271","doi-asserted-by":"crossref","first-page":"1241","DOI":"10.1242\/dev.125.7.1241","article-title":"FGF-, BMP- and Shh-mediated signalling pathways in the regulation of cranial suture morphogenesis and calvarial bone development","volume":"125","author":"Kim","year":"1998","journal-title":"Development"},{"key":"2021042501194737800_b25-0080271","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1111\/j.1755-0998.2010.02924.x","article-title":"MorphoJ: an integrated software package for geometric morphometrics","volume":"11","author":"Klingenberg","year":"2011","journal-title":"Mol. Ecol. Resour."},{"key":"2021042501194737800_b26-0080271","doi-asserted-by":"crossref","DOI":"10.1201\/9781420036176","volume-title":"An Invariant Approach to Statistical Analysis of Shapes","author":"Lele","year":"2001"},{"key":"2021042501194737800_b27-0080271","doi-asserted-by":"crossref","first-page":"784","DOI":"10.1002\/dvg.20768","article-title":"Indian hedgehog positively regulates calvarial ossification and modulates bone morphogenetic protein signaling","volume":"49","author":"Lenton","year":"2011","journal-title":"Genesis"},{"key":"2021042501194737800_b28-0080271","doi-asserted-by":"crossref","first-page":"5099","DOI":"10.1242\/dev.128.24.5099","article-title":"Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation","volume":"128","author":"Long","year":"2001","journal-title":"Development"},{"key":"2021042501194737800_b29-0080271","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1016\/j.devcel.2008.02.003","article-title":"Hedgehog signaling in mature osteoblasts regulates bone formation and resorption by controlling PTHrP and RANKL expression","volume":"14","author":"Mak","year":"2008","journal-title":"Dev. Cell"},{"key":"2021042501194737800_b30-0080271","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.ydbio.2005.04.030","article-title":"Molecular interactions coordinating the development of the forebrain and face","volume":"284","author":"Marcucio","year":"2005","journal-title":"Dev. Biol."},{"key":"2021042501194737800_b31-0080271","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1002\/ar.a.20231","article-title":"Developmentally regulated expression of Shh and Ihh in the developing mouse cranial base: comparison with Sox9 expression","volume":"286A","author":"Nie","year":"2005","journal-title":"Anat. Rec."},{"key":"2021042501194737800_b32-0080271","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1126\/science.1098992","article-title":"A chromosome 21 critical region does not cause specific Down syndrome phenotypes","volume":"306","author":"Olson","year":"2004","journal-title":"Science"},{"key":"2021042501194737800_b33-0080271","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3389\/fphys.2013.00061","article-title":"A review of hedgehog signaling in cranial bone development","volume":"4","author":"Pan","year":"2013","journal-title":"Front. Physiol."},{"key":"2021042501194737800_b34-0080271","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrg1525","article-title":"Down syndrome and genetics \u2013 a case of linked histories","volume":"6","author":"Patterson","year":"2005","journal-title":"Nat. Rev. Genet."},{"key":"2021042501194737800_b35-0080271","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1038\/ng1095-177","article-title":"A mouse model for Down syndrome exhibits learning and behaviour deficits","volume":"11","author":"Reeves","year":"1995","journal-title":"Nat. Genet."},{"key":"2021042501194737800_b36-0080271","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1007\/s00335-011-9357-z","article-title":"Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn","volume":"22","author":"Reinholdt","year":"2011","journal-title":"Mamm. Genome"},{"key":"2021042501194737800_b37-0080271","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1002\/(SICI)1097-0177(200002)217:2<137::AID-DVDY1>3.0.CO;2-N","article-title":"Parallels of craniofacial maldevelopment in Down syndrome and Ts65Dn mice","volume":"217","author":"Richtsmeier","year":"2000","journal-title":"Dev. Dyn."},{"key":"2021042501194737800_b38-0080271","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1073\/pnas.0510750103","article-title":"Defective cerebellar response to mitogenic Hedgehog signaling in Down [corrected] syndrome mice","volume":"103","author":"Roper","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2021042501194737800_b39-0080271","doi-asserted-by":"crossref","first-page":"2411","DOI":"10.1091\/mbc.e06-08-0743","article-title":"Ihh\/Gli2 signaling promotes osteoblast differentiation by regulating Runx2 expression and function","volume":"18","author":"Shimoyama","year":"2007","journal-title":"Mol. Biol. Cell"},{"key":"2021042501194737800_b40-0080271","doi-asserted-by":"crossref","DOI":"10.1007\/0-387-27614-9","volume-title":"Modern Morphometrics in Physical Anthropology","author":"Slice","year":"2005"},{"key":"2021042501194737800_b41-0080271","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1101\/gad.13.16.2072","article-title":"Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation","volume":"13","author":"St-Jacques","year":"1999","journal-title":"Genes Dev."},{"key":"2021042501194737800_b42-0080271","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1002\/ajmg.a.36594","article-title":"Overlapping trisomies for human chromosome 21 orthologs produce similar effects on skull and brain morphology of Dp(16)1Yey and Ts65Dn mice","volume":"164","author":"Starbuck","year":"2014","journal-title":"Am. J. Med. Genet. A"},{"key":"2021042501194737800_b43-0080271","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1111\/j.1469-7580.2005.00484.x","article-title":"It\u2019s all in your head: new insights into craniofacial development and deformation","volume":"207","author":"Tapadia","year":"2005","journal-title":"J. Anat."},{"key":"2021042501194737800_b44-0080271","doi-asserted-by":"crossref","first-page":"1678","DOI":"10.1359\/JBMR.040706","article-title":"Targeted expression of SHH affects chondrocyte differentiation, growth plate organization, and Sox9 expression","volume":"19","author":"Tavella","year":"2004","journal-title":"J. Bone Miner. Res."},{"key":"2021042501194737800_b45-0080271","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1126\/science.273.5275.613","article-title":"Regulation of rate of cartilage differentiation by Indian hedgehog and PTH-related protein","volume":"273","author":"Vortkamp","year":"1996","journal-title":"Science"},{"key":"2021042501194737800_b46-0080271","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.ydbio.2006.07.028","article-title":"Indian and sonic hedgehogs regulate synchondrosis growth plate and cranial base development and function","volume":"299","author":"Young","year":"2006","journal-title":"Dev. Biol."},{"key":"2021042501194737800_b47-0080271","doi-asserted-by":"crossref","first-page":"3405","DOI":"10.1242\/dev.052340","article-title":"Quantitative analyses link modulation of sonic hedgehog signaling to continuous variation in facial growth and shape","volume":"137","author":"Young","year":"2010","journal-title":"Development"},{"key":"2021042501194737800_b48-0080271","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1242\/dev.099994","article-title":"Embryonic bauplans and the developmental origins of facial diversity and constraint","volume":"141","author":"Young","year":"2014","journal-title":"Development"}],"container-title":["Disease Models &amp; Mechanisms"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/8\/3\/271\/1868642\/271.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.017889\/2035795\/dmm_017889.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/journals.biologists.com\/dmm\/article-pdf\/doi\/10.1242\/dmm.017889\/2035795\/dmm_017889.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,25]],"date-time":"2022-04-25T11:44:06Z","timestamp":1650887046000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dmm\/article\/doi\/10.1242\/dmm.017889\/258769\/Acute-upregulation-of-hedgehog-signaling-in-mice"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,1,1]]},"references-count":48,"URL":"https:\/\/doi.org\/10.1242\/dmm.017889","relation":{},"ISSN":["1754-8411","1754-8403"],"issn-type":[{"type":"electronic","value":"1754-8411"},{"type":"print","value":"1754-8403"}],"subject":[],"published":{"date-parts":[[2015,1,1]]},"article-number":"dmm.017889"}}