title: Preaxial polydactyly following early gestational exposure to the smoothened agonist, SAG, in C57BL/6J mice.
abstract: While pharmacological activation of the Hedgehog (HH) signaling pathway may have therapeutic benefits for developmental and adult diseases, its teratogenic potential is of concern. The membrane molecule Smoothened (SMO) transduces HH signaling and can be acutely modulated by antagonists and agonists. The objective of the current experiments was to determine how maternal treatment with the Smo agonist, SAG, affects the developing limb.
  
  
  
  Pregnant C57BL/6J mice received a single injection of SAG (15, 17, or 20 mg/kg, i.p.) or its vehicle on gestational day (GD) 9.25, the time of limb bud induction. Embryos were examined on GD 15 for gross dysmorphology and skeletal staining was performed to visualize the number and type of digits on the fore- and hindlimbs. Additionally, in situ hybridization was performed 4 hr after GD 9.25 SAG administration to determine SAG's effects on Gli1 and Gli2 mRNA expression.
  
  
  
  The most prevalent effect of SAG was the dose-dependent induction of pre-axial polydactyly; defects ranged from a broad thumb to the duplication of two finger-like digits on the preaxial side of the thumb. The highest SAG dose was effective in ca. 80% of the embryos and increased Gli1 and Gli2 mRNA expression in the limb bud, with Gli1 mRNA being the most upregulated.
  
  
  
  Preaxial polydactyly can be caused in the developing embryo by acute maternal administration of a Smo agonist that activates HH signaling. These results are consistent with the preaxial polydactyly induced in developmental disorders associated with mutations in HH signaling genes.Birth Defects Research 109:49-54, 2017. © 2016 Wiley Periodicals, Inc.
authors: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
authors: Eric W
authors: EW
authors: Fish
authors: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.|Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.|Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina.
authors: Scott E
authors: SE
authors: Parnell
authors: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.|Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina.|Carolina Institute for Developmental Disabilities, University of North Carolina, Chapel Hill, North Carolina.
authors: Kathleen K
authors: KK
authors: Sulik
authors: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
authors: Lorinda K
authors: LK
authors: Baker
authors: Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina.
authors: Laura B
authors: LB
authors: Murdaugh
authors: Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central University, Durham, North Carolina.
authors: David
authors: D
authors: Lamson
authors: Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central University, Durham, North Carolina.
authors: Kevin P
authors: KP
authors: Williams
mesh_terms: D000818:Animals; D003514:Cyclohexylamines / Q000009:adverse effects* / Q000378:metabolism*; D005121:Extremities; D005260:Female; D006226:Hand Deformities / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins / Q000235:genetics; D018878:Limb Buds / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D017689:Polydactyly / Q000235:genetics / Q000503:physiopathology*; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D015398:Signal Transduction / Q000235:genetics; D000072086:Smoothened Receptor / Q000819:agonists / Q000378:metabolism; D013876:Thiophenes / Q000009:adverse effects* / Q000378:metabolism*; D013933:Thumb / Q000002:abnormalities / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics; D000071676:Zinc Finger Protein GLI1 / Q000187:drug effects / Q000235:genetics; D000075746:Zinc Finger Protein Gli2 / Q000187:drug effects / Q000235:genetics
chemical_list: D003514:Cyclohexylamines; C498520:Gli1 protein, mouse; C000618551:Gli2 protein, mouse; D053823:Hedgehog Proteins; C468918:SAG compound; D000072086:Smoothened Receptor; D013876:Thiophenes; D014157:Transcription Factors; D000071676:Zinc Finger Protein GLI1; D000075746:Zinc Finger Protein Gli2
keywords: Sonic Hedgehog; limb development; polydactyly; prenatal exposure; skeletal