title: Acute upregulation of hedgehog signaling in mice causes differential effects on cranial morphology.
abstract: Hedgehog (HH) signaling, and particularly signaling by sonic hedgehog (SHH), is implicated in several essential activities during morphogenesis, and its misexpression causes a number of developmental disorders in humans. In particular, a reduced mitogenic response of cerebellar granule cell precursors to SHH signaling in a mouse model for Down syndrome (DS), Ts65Dn, is substantially responsible for reduced cerebellar size. A single treatment of newborn trisomic mice with an agonist of the SHH pathway (SAG) normalizes cerebellar morphology and restores some cognitive deficits, suggesting a possible therapeutic application of SAG for treating the cognitive impairments of DS. Although the beneficial effects on the cerebellum are compelling, inappropriate activation of the HH pathway causes anomalies elsewhere in the head, particularly in the formation and patterning of the craniofacial skeleton. To determine whether an acute treatment of SAG has an effect on craniofacial morphology, we quantitatively analyzed the cranial form of adult euploid and Ts65Dn mice that were injected with either SAG or vehicle at birth. We found significant deformation of adult craniofacial shape in some animals that had received SAG at birth. The most pronounced differences between the treated and untreated mice were in the midline structures of the facial skeleton. The SAG-driven craniofacial dysmorphogenesis was dose-dependent and possibly incompletely penetrant at lower concentrations. Our findings illustrate that activation of HH signaling, even with an acute postnatal stimulation, can lead to localized dysmorphology of the skull by generating modular shape changes in the facial skeleton. These observations have important implications for translating HH-agonist-based treatments for DS.
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Nandini
authors.initials: N
authors.lastname: Singh
authors.affiliation: Johns Hopkins University School of Medicine, Institute of Genetic Medicine, Baltimore, MD 21287, USA.
authors.forename: Tara
authors.initials: T
authors.lastname: Dutka
authors.affiliation: Johns Hopkins University School of Medicine, Department of Physiology, Baltimore, MD 21205, USA.
authors.forename: Benjamin M
authors.initials: BM
authors.lastname: Devenney
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Kawasaki
authors.affiliation: Johns Hopkins University School of Medicine, Institute of Genetic Medicine, Baltimore, MD 21287, USA Johns Hopkins University School of Medicine, Department of Physiology, Baltimore, MD 21205, USA.
authors.forename: Roger H
authors.initials: RH
authors.lastname: Reeves
authors.affiliation: Department of Anthropology, Pennsylvania State University, University Park, PA 16802, USA jta10@psu.edu.
authors.forename: Joan T
authors.initials: JT
authors.lastname: Richtsmeier
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005145:Face; D005260:Female; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D051379:Mice; D025341:Principal Component Analysis; D015398:Signal Transduction; D012886:Skull / Q000033:anatomy & histology* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053823:Hedgehog Proteins
keywords: Craniofacial shape; Down syndrome; Geometric morphometrics; Hedgehog signaling