title: Characterization of subtle brain abnormalities in a mouse model of Hedgehog pathway antagonist-induced cleft lip and palate.
abstract: Subtle behavioral and cognitive deficits have been documented in patient cohorts with orofacial clefts (OFCs). Recent neuroimaging studies argue that these traits are associated with structural brain abnormalities but have been limited to adolescent and adult populations where brain plasticity during infancy and childhood may be a confounding factor. Here, we employed high resolution magnetic resonance microscopy to examine primary brain morphology in a mouse model of OFCs. Transient in utero exposure to the Hedgehog (Hh) signaling pathway antagonist cyclopamine resulted in a spectrum of facial dysmorphology, including unilateral and bilateral cleft lip and palate, cleft of the secondary palate only, and a non-cleft phenotype marked by midfacial hypoplasia. Relative to controls, cyclopamine-exposed fetuses exhibited volumetric differences in several brain regions, including hypoplasia of the pituitary gland and olfactory bulbs, hyperplasia of the forebrain septal region, and expansion of the third ventricle. However, in affected fetuses the corpus callosum was intact and normal division of the forebrain was observed. This argues that temporally-specific Hh signaling perturbation can result in typical appearing OFCs in the absence of holoprosencephaly--a condition classically associated with Hh pathway inhibition and frequently co-occurring with OFCs. Supporting the premise that some forms of OFCs co-occur with subtle brain malformations, these results provide a possible ontological basis for traits identified in clinical populations. They also argue in favor of future investigations into genetic and/or environmental modulation of the Hh pathway in the etiopathogenesis of orofacial clefting.
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America; Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lipinski
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Hunter T
authors.initials: HT
authors.lastname: Holloway
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America; Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Shonagh K
authors.initials: SK
authors.lastname: O'Leary-Moore
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Jacob J
authors.initials: JJ
authors.lastname: Ament
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Pecevich
authors.affiliation: Center for In Vivo Microscopy, Duke University, Durham, North Carolina, United States of America.
authors.forename: Gary P
authors.initials: GP
authors.lastname: Cofer
authors.affiliation: Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Francois
authors.initials: F
authors.lastname: Budin
authors.affiliation: Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Joshua L
authors.initials: JL
authors.lastname: Everson
authors.affiliation: Center for In Vivo Microscopy, Duke University, Durham, North Carolina, United States of America.
authors.forename: G Allan
authors.initials: GA
authors.lastname: Johnson
authors.affiliation: The Bowles Center for Alcohol Studies, University of North Carolina, Chapel Hill, North Carolina, United States of America; Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, North Carolina, United States of America.
authors.forename: Kathleen K
authors.initials: KK
authors.lastname: Sulik
mesh_terms: D000818:Animals; D001921:Brain / Q000002:abnormalities*; D002971:Cleft Lip / Q000139:chemically induced* / Q000150:complications; D002972:Cleft Palate / Q000139:chemically induced* / Q000150:complications; D056324:Diffusion Tensor Imaging; D004195:Disease Models, Animal; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors*; D008046:Lip / Q000002:abnormalities; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010159:Palate / Q000002:abnormalities; D014704:Veratrum Alkaloids
chemical_list: D053823:Hedgehog Proteins; D014704:Veratrum Alkaloids; C000541:cyclopamine