PMID- 27801979
OWN - NLM
STAT- MEDLINE
DCOM- 20180312
LR  - 20191210
IS  - 2472-1727 (Electronic)
VI  - 109
IP  - 1
DP  - 2017 Jan 20
TI  - Preaxial polydactyly following early gestational exposure to the smoothened 
      agonist, SAG, in C57BL/6J mice.
PG  - 49-54
LID - 10.1002/bdra.23571 [doi]
AB  - BACKGROUND: 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. METHODS: 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. 
      RESULTS: 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. 
      CONCLUSION: 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. (c) 2016 Wiley Periodicals, Inc.
CI  - (c) 2016 Wiley Periodicals, Inc.
FAU - Fish, Eric W
AU  - Fish EW
AD  - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, 
      North Carolina.
FAU - Parnell, Scott E
AU  - Parnell SE
AD  - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, 
      North Carolina.
AD  - Department of Cell Biology and Physiology, University of North Carolina, Chapel 
      Hill, North Carolina.
AD  - Carolina Institute for Developmental Disabilities, University of North Carolina, 
      Chapel Hill, North Carolina.
FAU - Sulik, Kathleen K
AU  - Sulik KK
AD  - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, 
      North Carolina.
AD  - Department of Cell Biology and Physiology, University of North Carolina, Chapel 
      Hill, North Carolina.
AD  - Carolina Institute for Developmental Disabilities, University of North Carolina, 
      Chapel Hill, North Carolina.
FAU - Baker, Lorinda K
AU  - Baker LK
AD  - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, 
      North Carolina.
FAU - Murdaugh, Laura B
AU  - Murdaugh LB
AD  - Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, 
      North Carolina.
FAU - Lamson, David
AU  - Lamson D
AD  - Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central 
      University, Durham, North Carolina.
FAU - Williams, Kevin P
AU  - Williams KP
AD  - Department of Pharmaceutical Sciences, BRITE Institute, North Carolina Central 
      University, Durham, North Carolina.
LA  - eng
GR  - K99 AA018697/AA/NIAAA NIH HHS/United States
GR  - R00 AA018697/AA/NIAAA NIH HHS/United States
GR  - U01 AA021651/AA/NIAAA NIH HHS/United States
GR  - U54 AA019765/AA/NIAAA NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Birth Defects Res
JT  - Birth defects research
JID - 101701004
RN  - 0 (Cyclohexylamines)
RN  - 0 (Gli1 protein, mouse)
RN  - 0 (Gli2 protein, mouse)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (SAG compound)
RN  - 0 (Smoothened Receptor)
RN  - 0 (Thiophenes)
RN  - 0 (Transcription Factors)
RN  - 0 (Zinc Finger Protein GLI1)
RN  - 0 (Zinc Finger Protein Gli2)
RN  - Polydactyly preaxial type 1
RN  - Thumb deformity
SB  - IM
MH  - Animals
MH  - Cyclohexylamines/*adverse effects/*metabolism
MH  - Extremities
MH  - Female
MH  - Hand Deformities/genetics/metabolism
MH  - Hedgehog Proteins/genetics
MH  - Limb Buds/metabolism
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mutation
MH  - Polydactyly/genetics/*physiopathology
MH  - Pregnancy
MH  - Prenatal Exposure Delayed Effects
MH  - Signal Transduction/genetics
MH  - Smoothened Receptor/agonists/metabolism
MH  - Thiophenes/*adverse effects/*metabolism
MH  - Thumb/abnormalities/physiopathology
MH  - Transcription Factors/genetics
MH  - Zinc Finger Protein GLI1/drug effects/genetics
MH  - Zinc Finger Protein Gli2/drug effects/genetics
PMC - PMC5388559
MID - NIHMS815756
OTO - NOTNLM
OT  - Sonic Hedgehog
OT  - limb development
OT  - polydactyly
OT  - prenatal exposure
OT  - skeletal
EDAT- 2016/11/02 06:00
MHDA- 2018/03/13 06:00
PMCR- 2018/01/20
CRDT- 2016/11/02 06:00
PHST- 2016/05/06 00:00 [received]
PHST- 2016/08/01 00:00 [revised]
PHST- 2016/08/29 00:00 [accepted]
PHST- 2016/11/02 06:00 [pubmed]
PHST- 2018/03/13 06:00 [medline]
PHST- 2016/11/02 06:00 [entrez]
PHST- 2018/01/20 00:00 [pmc-release]
AID - 10.1002/bdra.23571 [doi]
PST - ppublish
SO  - Birth Defects Res. 2017 Jan 20;109(1):49-54. doi: 10.1002/bdra.23571.