Characterization of subtle brain abnormalities in a mouse model of Hedgehog pathway antagonist-induced cleft lip and palate

• Published in: PloS one Vol. 9; no. 7; p. e102603
• Main Authors: Lipinski, Robert J, Holloway, Hunter T, O'Leary-Moore, Shonagh K, Ament, Jacob J, Pecevich, Stephen J, Cofer, Gary P, Budin, Francois, Everson, Joshua L, Johnson, G Allan, Sulik, Kathleen K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 21-07-2014; Public Library of Science (PLoS)
• Subjects: Abnormalities; Alcohol; Animals; Behavioral plasticity; Biology and Life Sciences; Birth defects; Brain; Brain - abnormalities; Brain research; Children; Cleft Lip - chemically induced; Cleft Lip - complications; Cleft lip/palate; Cleft Palate - chemically induced; Cleft Palate - complications; Cognitive ability; Corpus callosum; Diffusion Tensor Imaging; Disease Models, Animal; Female; Fetuses; Forebrain; Growth hormones; Hedgehog protein; Hedgehog Proteins - antagonists & inhibitors; Holoprosencephaly; Hyperplasia; Hypoplasia; Intrauterine exposure; Lip - abnormalities; Magnetic resonance; Magnetic Resonance Imaging; Male; Medical imaging; Medicine and Health Sciences; Mice; Mice, Inbred C57BL; Microscopy; Morphology; Mutation; Neuroimaging; Neurology; Olfactory bulb; Orofacial clefts; Palate - abnormalities; Pediatrics; Phenotypes; Pituitary; Pituitary gland; Populations; Signal transduction; Signaling; Ventricle; Ventricles (cerebral); Veratrum Alkaloids; North Carolina; United States > US; Wisconsin
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0102603

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.