title: Quantitative analyses link modulation of sonic hedgehog signaling to continuous variation in facial growth and shape.
abstract: Variation is an intrinsic feature of biological systems, yet developmental biology does not frequently address population-level phenomena. Sonic hedgehog (SHH) signaling activity in the vertebrate forebrain and face is thought to contribute to continuous variation in the morphology of the upper jaw, but despite its potential explanatory power, this idea has never been quantitatively assessed. Here, we test this hypothesis with an experimental design that is explicitly focused on the generation and measurement of variation in multivariate shape, tissue growth, cellular behavior and gene expression. We show that the majority of upper jaw shape variation can be explained by progressive changes in the spatial organization and mitotic activity of midfacial growth zones controlled by SHH signaling. In addition, nonlinearity between our treatment doses and phenotypic outcomes suggests that threshold effects in SHH signaling may play a role in variability in midfacial malformations such as holoprosencephaly (HPE). Together, these results provide novel insight into the generation of facial morphology, and demonstrate the value of quantifying variation for our understanding of development and disease.
authors.affiliation: Department of Orthopaedic Surgery, University of California-San Francisco, 2550 23rd Street, San Francisco, CA 94110, USA.
authors.forename: Nathan M
authors.initials: NM
authors.lastname: Young
authors.forename: H Jonathan
authors.initials: HJ
authors.lastname: Chong
authors.forename: Diane
authors.initials: D
authors.lastname: Hu
authors.forename: Benedikt
authors.initials: B
authors.lastname: Hallgrímsson
authors.forename: Ralph S
authors.initials: RS
authors.lastname: Marcucio
mesh_terms: D000818:Animals; D001837:Body Weights and Measures; D049109:Cell Proliferation; D002642:Chick Embryo; D017931:DNA Primers / Q000235:genetics; D005147:Facial Bones / Q000196:embryology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D017931:DNA Primers; D053823:Hedgehog Proteins
references.citation: Pediatrics. 1964 Aug;34:256-63
references.pmid: 14211086
references.citation: Dev Biol. 2008 Sep 15;321(2):295-302
references.pmid: 18619435
references.citation: Development. 2005 Jan;132(1):133-42
references.pmid: 15576405
references.citation: J Clin Invest. 2004 Aug;114(4):485-94
references.pmid: 15314685
references.citation: N Engl J Med. 2009 Apr 23;360(17):1759-68
references.pmid: 19369657
references.citation: Nat Rev Mol Cell Biol. 2005 Apr;6(4):306-17
references.pmid: 15803137
references.citation: Nature. 2002 Aug 22;418(6900):892-7
references.pmid: 12192414
references.citation: Dev Biol. 2009 Jun 1;330(1):200-11
references.pmid: 19285488
references.citation: Development. 2003 May;130(9):1749-58
references.pmid: 12642481
references.citation: Genes Dev. 2007 May 15;21(10):1244-57
references.pmid: 17504941
references.citation: J Clin Invest. 2007 Jun;117(6):1575-84
references.pmid: 17525797
references.citation: Development. 2004 Aug;131(16):4021-33
references.pmid: 15269168
references.citation: Dev Cell. 2006 May;10(5):647-56
references.pmid: 16647304
references.citation: Dev Cell. 2006 May;10(5):657-65
references.pmid: 16647303
references.citation: J Craniofac Genet Dev Biol. 1992 Oct-Dec;12(4):196-244
references.pmid: 1494025
references.citation: Curr Opin Genet Dev. 2000 Jun;10(3):262-9
references.pmid: 10826992
references.citation: Proc Natl Acad Sci U S A. 2008 May 6;105(18):6714-9
references.pmid: 18443298
references.citation: Development. 2009 Jan;136(1):107-16
references.pmid: 19036802
references.citation: Ment Retard Dev Disabil Res Rev. 2000;6(1):15-21
references.pmid: 10899793
references.citation: Am J Med Genet A. 2008 Mar 1;146A(5):548-57
references.pmid: 18241058
references.citation: Biophys J. 2004 May;86(5):2748-57
references.pmid: 15111393
references.citation: Am J Hum Genet. 2002 Nov;71(5):1017-32
references.pmid: 12395298
references.citation: Dev Cell. 2003 Oct;5(4):635-46
references.pmid: 14536064
references.citation: Anat Rec (Hoboken). 2007 Jan;290(1):123-39
references.pmid: 17441205
references.citation: Nat Rev Genet. 2009 Aug;10(8):517-30
references.pmid: 19584811
references.citation: Cell Cycle. 2007 Nov 1;6(21):2640-9
references.pmid: 17912034
references.citation: J Anat. 2008 Feb;212(2):135-43
references.pmid: 18093101
references.citation: Dev Biol. 2005 Aug 1;284(1):48-61
references.pmid: 15979605
references.citation: Development. 2010 Jan;137(1):133-40
references.pmid: 20023168
references.citation: Development. 2006 Mar;133(5):889-900
references.pmid: 16452094
references.citation: J Anat. 2008 Dec;213(6):646-62
references.pmid: 19094181
references.citation: Genes Dev. 2001 Dec 1;15(23):3059-87
references.pmid: 11731473
references.citation: J Clin Invest. 2008 May;118(5):1590-605
references.pmid: 18451988
references.citation: Am J Hum Genet. 2000 Jun;66(6):1729-35
references.pmid: 10793008
references.citation: Curr Top Dev Biol. 2003;53:1-114
references.pmid: 12509125