PMID- 25793997
OWN - NLM
STAT- MEDLINE
DCOM- 20160208
LR  - 20181113
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 10
IP  - 3
DP  - 2015
TI  - Definition of critical periods for Hedgehog pathway antagonist-induced 
      holoprosencephaly, cleft lip, and cleft palate.
PG  - e0120517
LID - 10.1371/journal.pone.0120517 [doi]
LID - e0120517
AB  - The Hedgehog (Hh) signaling pathway mediates multiple spatiotemporally-specific 
      aspects of brain and face development. Genetic and chemical disruptions of the 
      pathway are known to result in an array of structural malformations, including 
      holoprosencephaly (HPE), clefts of the lip with or without cleft palate (CL/P), 
      and clefts of the secondary palate only (CPO). Here, we examined patterns of 
      dysmorphology caused by acute, stage-specific Hh signaling inhibition. 
      Timed-pregnant wildtype C57BL/6J mice were administered a single dose of the 
      potent pathway antagonist vismodegib at discrete time points between gestational 
      day (GD) 7.0 and 10.0, an interval approximately corresponding to the 15th to 
      24th days of human gestation. The resultant pattern of facial and brain 
      dysmorphology was dependent upon stage of exposure. Insult between GD7.0 and 
      GD8.25 resulted in HPE, with peak incidence following exposure at GD7.5. 
      Unilateral clefts of the lip extending into the primary palate were also 
      observed, with peak incidence following exposure at GD8.875. Insult between GD9.0 
      and GD10.0 resulted in CPO and forelimb abnormalities. We have previously 
      demonstrated that Hh antagonist-induced cleft lip results from deficiency of the 
      medial nasal process and show here that CPO is associated with reduced growth of 
      the maxillary-derived palatal shelves. By defining the critical periods for the 
      induction of HPE, CL/P, and CPO with fine temporal resolution, these results 
      provide a mechanism by which Hh pathway disruption can result in "non-syndromic" 
      orofacial clefting, or HPE with or without co-occurring clefts. This study also 
      establishes a novel and tractable mouse model of human craniofacial malformations 
      using a single dose of a commercially available and pathway-specific drug.
FAU - Heyne, Galen W
AU  - Heyne GW
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Melberg, Cal G
AU  - Melberg CG
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Doroodchi, Padydeh
AU  - Doroodchi P
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Parins, Kia F
AU  - Parins KF
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Kietzman, Henry W
AU  - Kietzman HW
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Everson, Joshua L
AU  - Everson JL
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America; Molecular and 
      Environmental Toxicology Center, School of Medicine and Public Health, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Ansen-Wilson, Lydia J
AU  - Ansen-Wilson LJ
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
FAU - Lipinski, Robert J
AU  - Lipinski RJ
AD  - Department of Comparative Biosciences, School of Veterinary Medicine, University 
      of Wisconsin-Madison, Madison, WI, United States of America; Molecular and 
      Environmental Toxicology Center, School of Medicine and Public Health, University 
      of Wisconsin-Madison, Madison, WI, United States of America.
LA  - eng
GR  - R00 DE022101/DE/NIDCR NIH HHS/United States
GR  - T32 ES007015/ES/NIEHS NIH HHS/United States
GR  - R00DE022101-02/DE/NIDCR NIH HHS/United States
GR  - T32ES007015-37/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20150320
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Anilides)
RN  - 0 (Hedgehog Proteins)
RN  - 0 (HhAntag691)
RN  - 0 (Pyridines)
SB  - IM
MH  - Anilides/*adverse effects
MH  - Animals
MH  - Cleft Lip/chemically induced/metabolism/*pathology
MH  - Cleft Palate/chemically induced/metabolism/*pathology
MH  - Face/abnormalities
MH  - Female
MH  - Hedgehog Proteins/*antagonists & inhibitors/metabolism
MH  - Holoprosencephaly/chemically induced/metabolism/*pathology
MH  - Mice, Inbred C57BL
MH  - Morphogenesis/drug effects
MH  - Phenotype
MH  - Pregnancy
MH  - Pyridines/*adverse effects
MH  - *Signal Transduction/drug effects
PMC - PMC4368540
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2015/03/21 06:00
MHDA- 2016/02/09 06:00
PMCR- 2015/03/20
CRDT- 2015/03/21 06:00
PHST- 2014/11/24 00:00 [received]
PHST- 2015/02/04 00:00 [accepted]
PHST- 2015/03/21 06:00 [entrez]
PHST- 2015/03/21 06:00 [pubmed]
PHST- 2016/02/09 06:00 [medline]
PHST- 2015/03/20 00:00 [pmc-release]
AID - PONE-D-14-52130 [pii]
AID - 10.1371/journal.pone.0120517 [doi]
PST - epublish
SO  - PLoS One. 2015 Mar 20;10(3):e0120517. doi: 10.1371/journal.pone.0120517. 
      eCollection 2015.