PMID- 20213699
OWN - NLM
STAT- MEDLINE
DCOM- 20100721
LR  - 20181113
IS  - 1542-0760 (Electronic)
IS  - 1542-0752 (Print)
IS  - 1542-0752 (Linking)
VI  - 88
IP  - 4
DP  - 2010 Apr
TI  - Cleft lip and palate results from Hedgehog signaling antagonism in the mouse: 
      Phenotypic characterization and clinical implications.
PG  - 232-40
LID - 10.1002/bdra.20656 [doi]
AB  - BACKGROUND: The Hedgehog (Hh) pathway provides inductive signals critical for 
      developmental patterning of the brain and face. In humans and in animal models 
      interference with this pathway yields birth defects, among the most well-studied 
      of which fall within the holoprosencephaly (HPE) spectrum. METHODS: 
      Timed-pregnant C57Bl/6J mice were treated with the natural Hh signaling 
      antagonist cyclopamine by subcutaneous infusion from gestational day (GD) 8.25 to 
      9.5, or with a potent cyclopamine analog, AZ75, administered by oral gavage at GD 
      8.5. Subsequent embryonic morphogenesis and fetal central nervous system (CNS) 
      phenotype were respectively investigated by scanning electron microscopy and high 
      resolution magnetic resonance imaging (MRI). RESULTS: In utero Hh signaling 
      antagonist exposure induced a spectrum of craniofacial and brain malformations. 
      Cyclopamine exposure caused lateral cleft lip and palate (CLP) defects 
      attributable to embryonic deficiency of midline and lower medial nasal prominence 
      tissue. The CLP phenotype was accompanied by olfactory bulb hypoplasia and 
      anterior pituitary aplasia, but otherwise grossly normal brain morphology. AZ75 
      exposure caused alobar and semilobar HPE with associated median facial 
      deficiencies. An intermediate phenotype of median CLP was produced infrequently 
      by both drug administration regimens. CONCLUSIONS: The results of this study 
      suggest that interference with Hh signaling should be considered in the CLP 
      differential and highlight the occurrence of CNS defects that are expected to be 
      present in a cohort of patients having CLP. This work also illustrates the 
      utility of fetal MRI-based analyses and establishes a novel mouse model for 
      teratogen-induced CLP.
CI  - (c) 2010 Wiley-Liss, Inc.
FAU - Lipinski, Robert J
AU  - Lipinski RJ
AD  - Molecular and Environmental Toxicology Center, School of Medicine and Public 
      Health, University of Wisconsin, Madison, WI, USA. Lipinski@med.unc.edu
FAU - Song, Chihwa
AU  - Song C
FAU - Sulik, Kathleen K
AU  - Sulik KK
FAU - Everson, Joshua L
AU  - Everson JL
FAU - Gipp, Jerry J
AU  - Gipp JJ
FAU - Yan, Dong
AU  - Yan D
FAU - Bushman, Wade
AU  - Bushman W
FAU - Rowland, Ian J
AU  - Rowland IJ
LA  - eng
GR  - P50 DK065303/DK/NIDDK NIH HHS/United States
GR  - AA007573/AA/NIAAA NIH HHS/United States
GR  - T32-ES007015/ES/NIEHS NIH HHS/United States
GR  - P60 AA011605/AA/NIAAA NIH HHS/United States
GR  - P60 AA011605-090004/AA/NIAAA NIH HHS/United States
GR  - R01 DK056238-08/DK/NIDDK NIH HHS/United States
GR  - T32 AA007573-13/AA/NIAAA NIH HHS/United States
GR  - AA011605/AA/NIAAA NIH HHS/United States
GR  - T32 ES007015-28/ES/NIEHS NIH HHS/United States
GR  - P50 AA011605/AA/NIAAA NIH HHS/United States
GR  - U01 AA017124/AA/NIAAA NIH HHS/United States
GR  - T32 AA007573/AA/NIAAA NIH HHS/United States
GR  - R01 DK056238/DK/NIDDK NIH HHS/United States
GR  - U01 AA017124-03/AA/NIAAA NIH HHS/United States
GR  - AA017124/AA/NIAAA NIH HHS/United States
GR  - P50 DK065303-05/DK/NIDDK NIH HHS/United States
GR  - P60 AA011605-110004/AA/NIAAA NIH HHS/United States
GR  - T32 ES007015/ES/NIEHS NIH HHS/United States
GR  - DK065303/DK/NIDDK NIH HHS/United States
GR  - DK056238/DK/NIDDK NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Birth Defects Res A Clin Mol Teratol
JT  - Birth defects research. Part A, Clinical and molecular teratology
JID - 101155107
RN  - 0 (Hedgehog Proteins)
RN  - 0 (Veratrum Alkaloids)
RN  - ZH658AJ192 (cyclopamine)
SB  - IM
MH  - Abnormalities, Drug-Induced/embryology/*etiology/physiopathology
MH  - Abnormalities, Multiple/*chemically induced/embryology/physiopathology
MH  - Administration, Oral
MH  - Animals
MH  - Cells, Cultured/drug effects
MH  - Cleft Lip/*chemically induced/embryology/physiopathology
MH  - Cleft Palate/*chemically induced/embryology/physiopathology
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Female
MH  - Fetal Resorption/chemically induced
MH  - Fetus/drug effects/ultrastructure
MH  - Hedgehog Proteins/*antagonists & inhibitors/physiology
MH  - Holoprosencephaly/*chemically induced/embryology/physiopathology
MH  - Maternal Exposure/*adverse effects
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Microscopy, Electron, Scanning
MH  - NIH 3T3 Cells/drug effects
MH  - Olfactory Bulb/*abnormalities/embryology
MH  - Phenotype
MH  - Pituitary Gland, Anterior/*abnormalities/embryology
MH  - Veratrum Alkaloids/administration & dosage/pharmacology/*toxicity
PMC - PMC2922848
MID - NIHMS224153
EDAT- 2010/03/10 06:00
MHDA- 2010/07/22 06:00
PMCR- 2011/04/01
CRDT- 2010/03/10 06:00
PHST- 2010/03/10 06:00 [entrez]
PHST- 2010/03/10 06:00 [pubmed]
PHST- 2010/07/22 06:00 [medline]
PHST- 2011/04/01 00:00 [pmc-release]
AID - 10.1002/bdra.20656 [doi]
PST - ppublish
SO  - Birth Defects Res A Clin Mol Teratol. 2010 Apr;88(4):232-40. doi: 
      10.1002/bdra.20656.