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WIREs Dev Biol
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Unmasking the ciliopathies: craniofacial defects and the primary cilium

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Over the past decade, the primary cilium has emerged as a pivotal sensory organelle that acts as a major signaling hub for a number of developmental signaling pathways. In that time, a vast number of proteins involved in trafficking and signaling have been linked to ciliary assembly and/or function, demonstrating the importance of this organelle during embryonic development. Given the central role of the primary cilium in regulating developmental signaling, it is not surprising that its dysfunction results in widespread defects in the embryo, leading to an expanding class of human congenital disorders known as ciliopathies. These disorders are individually rare and phenotypically variable, but together they affect virtually every vertebrate organ system. Features of ciliopathies that are often overlooked, but which are being reported with increasing frequency, are craniofacial abnormalities, ranging from subtle midline defects to full‐blown orofacial clefting. The challenge moving forward is to understand the primary mechanism of disease given the link between the primary cilium and a number of developmental signaling pathways (such as hedgehog, platelet‐derived growth factor, and WNT signaling) that are essential for craniofacial development. Here, we provide an overview of the diversity of craniofacial abnormalities present in the ciliopathy spectrum, and reveal those defects in common across multiple disorders. Further, we discuss the molecular defects and potential signaling perturbations underlying these anomalies. This provides insight into the mechanisms leading to ciliopathy phenotypes more generally and highlights the prevalence of widespread dysmorphologies resulting from cilia dysfunction. WIREs Dev Biol 2015, 4:637–653. doi: 10.1002/wdev.199 This article is categorized under: Birth Defects > Craniofacial and Nervous System Anomalies Birth Defects > Organ Anomalies
Fusion and merging of the facial prominences and their contribution to the mature face. Scanning electron micrograph of an E10.5 mouse embryo in the frontal plane (the heart has been dissected off to view the face). Dark and light blue arrows mark sites of fusion and red, yellow, and orange arrows mark sites of merging of facial prominences to form the mature face (see text for description). fb, forebrain; lnp, lateral nasal process; md, mandible; mnp, medial nasal process; mx, maxilla; n, nasal pit; pa2, second pharyngeal arch. Table indicates the contribution of each prominence to the mature face.
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Development of the facial primordia. (a)–(e) Scanning electron micrographs showing how the primitive face emerges in mouse embryos. A summary of the major developmental processes that occur at the respective stages is included below (see text for description). Dashed lines in (b) demarcate the approximate position where the nasal placodes will appear. By E10.25 (c) the nasal placode is beginning to invaginate. By E10.5 (d) the nasal placodes have invaginated to form nasal pits and two distinct medial nasal processes and lateral nasal processes have emerged. By E11.5 (e) the nasal pits have formed nasal slits and the various prominences are continuing to merge and fuse as described in the text. fb, forebrain; lnp, lateral nasal process; mb, midbrain; md, mandible; mnp, medial nasal process; mx, maxilla; n, nasal pit; p, nasal placode; pa1, first pharyngeal arch; pa2, second pharyngeal arch. Scale bars represent 100 µm.
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Craniofacial features are widespread in ciliopathies. Venn diagram of craniofacial aspects of ciliopathies. Those ciliopathies with craniofacial defects all have reports of hypertelorism and lip/palatal defects with the exception of Ellis–van Creveld (EVC)**. Note: JATD, Sensenbrenner, EVC, and SRPS have been grouped as ‘skeletal ciliopathies’.
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Structure and disease‐associated compartments of the primary cilium. (a) The cilium is composed of nine microtubule doublets (axoneme) that extend from the basal body, a modified mother centriole. Proteins required for cilium biogenesis and function are trafficked along the axoneme by intraflagellar transport (IFT). Anterograde IFT is driven by the Kinesin‐II motor and IFT‐B proteins; retrograde IFT involves a Dynein motor and IFT‐A proteins. IFT complexes are organized at the transition zone, which also acts as a diffusion barrier between the axoneme and the cytoplasm. The BBSome is a vesicle coat‐like complex that regulates trafficking to the cilium and also moves along the axoneme tethered to IFT particles. The Golgi complex and the pericentrosomal preciliary compartment (PPC) contribute proteins to the base of the cilium. (b) Dysfunction of proteins localizing to most ciliary compartments causes ciliopathies associated with craniofacial defects. However, there is some phenotypic overlap between syndromes associated with proteins localizing to similar compartments or influencing certain functions [e.g., Meckel‐Gruber syndrome (MKS) and Joubert syndromes at the transition zone and centrioles/basal body; skeletal ciliopathies and IFT].
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