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WIREs Dev Biol
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Holoprosencephaly: signaling interactions between the brain and the face, the environment and the genes, and the phenotypic variability in animal models and humans

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Holoprosencephaly (HPE) is the most common developmental defect of the forebrain characterized by inadequate or absent midline division of the forebrain into cerebral hemispheres, with concomitant midline facial defects in the majority of cases. Understanding the pathogenesis of HPE requires knowledge of the relationship between the developing brain and the facial structures during embryogenesis. A number of signaling pathways control and coordinate the development of the brain and face, including Sonic hedgehog, Bone morphogenetic protein, Fibroblast growth factor, and Nodal signaling. Mutations in these pathways have been identified in animal models of HPE and human patients. Because of incomplete penetrance and variable expressivity of HPE, patients carrying defined mutations may not manifest the disease at all, or have a spectrum of defects. It is currently unknown what drives manifestation of HPE in genetically at‐risk individuals, but it has been speculated that other gene mutations and environmental factors may combine as cumulative insults. HPE can be diagnosed in utero by a high‐resolution prenatal ultrasound or a fetal magnetic resonance imaging, sometimes in combination with molecular testing from chorionic villi or amniotic fluid sampling. Currently, there are no effective preventive methods for HPE. Better understanding of the mechanisms of gene–environment interactions in HPE would provide avenues for such interventions. WIREs Dev Biol 2015, 4:17–32. doi: 10.1002/wdev.161 This article is categorized under: Nervous System Development > Vertebrates: General Principles Birth Defects > Craniofacial and Nervous System Anomalies
Holoprosencephaly in humans and mice. (a) Normal human brain magnetic resonance imaging (MRI). The two cerebral hemispheres are completely separated. The septum (arrow) and the corpus callosum (arrowhead) are present. (Reprinted with permission from Ref . Copyright 2009 American Society for Clinical Investigation). (b) MRI of a neonate with alobar holoprosencephaly (HPE) showing a monoventricle (MV) and a large dorsal cyst (DC) posteriorly. (Reprinted with permission from Ref . Copyright 2010 John Wiley and Sons). (c) Transverse section of wild‐type mouse brain at birth. (d) Nonseparation of the brain and a large monoventricle in Twsg1−/− mouse at birth (c and d: Reprinted with permission from Ref . Copyright 2004 Elsevier)
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Schematic representation of core pathways involved in forebrain development and holoprosencephaly (HPE). Classic HPE‐related pathways that signal predominantly at the ventral midline are shown in orange. The bone morphogenetic protein (BMP) pathway is shown in blue signals predominantly at the dorsal midline and is involved in midline interhemispheric (MIH) HPE. (Reprinted with permission from Ref . Copyright 2008 John Wiley and Sons)
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Nonlinearities in signaling may produce phenotypic variation. A model illustrating how nonlinear properties of a signaling pathway can produce phenotypic variation. By reducing SHH signaling a large amount of phenotypic variance could be produced owing to the nonlinear nature of the SHH pathway. (Reprinted with permission from Ref . Copyright 2009 Springer)
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Signaling centers instructing telencephalon. Frontolateral view of the telencephalon indicating its distinct signaling centers important for regional differentiation in relation to other developing head structures: the ventral center secreting SHH (red), the rostral center secreting FGF8 (blue), and the dorsal center secreting BMPs and Wnt (green). Cross‐regulation between the rostral, dorsal, and ventral signaling centers plays an essential role in patterning the early telencephalon. Cx, cortex; LGE, lateral ganglionic eminence; MGE, medial ganglionic eminence; S, septum. (Reprinted with permission from Ref . Copyright 2009 Elsevier)
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Spatial relationships during development of the head. (a) A bright field image of a HH10 chicken embryo in ovo. Dorsal view showing regionalization of the neural tube into the prosencephalon (p), mesencephalon (ms), and metencephalon (mt). The anterior neural pore (anp) is located at the anterior end of the neural tube, and the neural tube is flanked by paraxial mesoderm (pm). (b) A sagittal section of a HH10 embryo that has been stained with bis‐benzimide and imaged using an epifluorescent microscope (Leica) showing the prosencephalon (p), mesencephalon (ms), the anterior neural pore (anp), the pharyngeal endoderm (pe), the facial ectoderm (fe), and the prechordal mesoderm (asterisk).
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Spectrum of craniofacial phenotypes in humans (a–e) and Twsg1−/− mice (f–j). (a) Single central incisor; (b) microcephaly, midface hypoplasia with bilateral cleft lip and palate; (c) cyclopia with proboscis above the fused eye; and (d) hypotelorism and a single nostril. (a–d: Reprinted with permission from Ref . Copyright 2000 John Wiley and Sons). (e) Agnathia with downward displacement of the ears and microstomia. (Reprinted with permission from Ref . Copyright 2002 John Wiley and Sons). (f) Wild type; (g) severe anterior truncation; (h) cyclopia with proboscis; (i) single nostril with agnathia; and (j) agnathia. (f–j: Reprinted with permission from Ref . Copyright 2004 Elsevier)
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Nervous System Development > Vertebrates: General Principles
Birth Defects > Craniofacial and Nervous System Anomalies