The emerging face of primary cilia

Department of Medicine, Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland, USA.
genesis (Impact Factor: 2.02). 04/2011; 49(4):231-46. DOI: 10.1002/dvg.20728
Source: PubMed


Primary cilia are microtubule-based organelles that serve as hubs for the transduction of various developmental signaling pathways including Hedgehog, Wnt, FGF, and PDGF. Ciliary dysfunction contributes to a range of disorders, collectively known as the ciliopathies. Recently, interest has grown in these syndromes, particularly among craniofacial biologists, as many known and putative ciliopathies have severe craniofacial defects. Herein we discuss the current understanding of ciliary biology and craniofacial development in an attempt to gain insight into the molecular etiology for craniofacial ciliopathies, and uncover a characteristic ciliopathic craniofacial gestalt.

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    • "Notably, radial glia and their progeny (ependymal and neural progenitor cells) strongly express FGFR1 (Zheng et al. 2004; García-González et al. 2010; Gálvez- Contreras et al. 2012) and FGFR1 signalling regulates cilia length and function in diverse epithelia during development (Neugebauer et al. 2009). Moreover, FGFR1 is expressed in the motile cilia and FGF signalling is associated with tumour progression and several ciliopathies (Trumpp et al. 1999; Evans et al. 2002; Macatee et al. 2003; Creuzet et al. 2004; Szabo-Rogers et al. 2008; Zaghloul and Brugmann 2011). Hence, FGFR1 expression in ependymal cells may actually be important for ependymal ciliary beating in the lateral ventricles. "
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    ABSTRACT: New subventricular zone (SVZ)-derived neuroblasts that migrate via the rostral migratory stream are continuously added to the olfactory bulb (OB) of the adult rodent brain. Anosmin-1 (A1) is an extracellular matrix protein that binds to FGF receptor 1 (FGFR1) to exert its biological effects. When mutated as in Kallmann syndrome patients, A1 is associated with severe OB morphogenesis defects leading to anosmia and hypogonadotropic hypogonadism. Here, we show that A1 over-expression in adult mice strongly increases proliferation in the SVZ, mainly with symmetrical divisions, and produces substantial morphological changes in the normal SVZ architecture, where we also report the presence of FGFR1 in almost all SVZ cells. Interestingly, for the first time we show FGFR1 expression in the basal body of primary cilia in neural progenitor cells. Additionally, we have found that A1 over-expression also enhances neuroblast motility, mainly through FGFR1 activity. Together, these changes lead to a selective increase in several GABAergic interneuron populations in different OB layers. These specific alterations in the OB would be sufficient to disrupt the normal processing of sensory information and consequently alter olfactory memory. In summary, this work shows that FGFR1-mediated A1 activity plays a crucial role in the continuous remodelling of the adult OB.
    Brain Structure and Function 10/2014; DOI:10.1007/s00429-014-0904-8 · 5.62 Impact Factor
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    • "While little is known about the genetic or environmental causes of median facial clefts, human cases of median orofacial clefts have been associated with retinoic acid and vitamin D deficiencies, as well as genetic mutations in Fgf receptors, Alx gene family members and the Six2 transcription factor (Beverdam et al., 2001; Fogelgren et al., 2008; Snyder-Warwick et al., 2010; Twigg et al., 2009). A literature review also uncovered other affected genes in vertebrates displaying median clefts such as PDGF, kif3a, gli3, lhx8 and msx2 (Brugmann et al., 2010; Eberhart et al., 2008; Winograd et al., 1997; Zaghloul and Brugmann, 2011; Zhao et al., 1999). Genetically or mechanistically , it has been unclear whether there are any connections between these genes during upper lip and palate development. "
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    ABSTRACT: The upper lip and primary palate form an essential separation between the brain, nasal structures and the oral cavity. Surprisingly little is known about the development of these structures, despite the fact that abnormalities can result in various forms of orofacial clefts. We have uncovered that retinoic acid is a critical regulator of upper lip and primary palate development in Xenopus laevis. Retinoic acid synthesis enzyme, RALDH2, and retinoic acid receptor gamma (RARγ) are expressed in complementary and partially overlapping regions of the orofacial prominences that fate mapping revealed contribute to the upper lip and primary palate. Decreased RALDH2 and RARγ result in a median cleft in the upper lip and primary palate. To further understand how retinoic acid regulates upper lip and palate morphogenesis we searched for genes downregulated in response to RARγ inhibition in orofacial tissue, and uncovered homeobox genes lhx8 and msx2. These genes are both expressed in overlapping domains with RARγ, and together their loss of function also results in a median cleft in the upper lip and primary palate. Inhibition of RARγ and decreased Lhx8/Msx2 function result in decreased cell proliferation and failure of dorsal anterior cartilages to form. These results suggest a model whereby retinoic acid signaling regulates Lhx8 and Msx2, which together direct the tissue growth and differentiation necessary for the upper lip and primary palate morphogenesis. This work has the potential to better understand the complex nature of the upper lip and primary palate development which will lead to important insights into the etiology of human orofacial clefts.
    Developmental Biology 03/2012; 365(1):229-40. DOI:10.1016/j.ydbio.2012.02.033 · 3.55 Impact Factor
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    ABSTRACT: Two positional characteristics of the ciliary axoneme--its location on the plasma membrane as it emerges from the cell, and its orientation in three-dimensional (3D) space--are known to be critical for optimal function of actively motile cilia (including nodal cilia), as well as for modified cilia associated with special senses. However, these positional characteristics have not been analyzed to any significant extent for primary cilia. This review briefly summarizes the history of knowledge of these two positional characteristics across a wide spectrum of cilia, emphasizing their importance for proper function. Then the review focuses what is known about these same positional characteristics for primary cilia in all major tissue types where they have been reported. The review emphasizes major areas that would be productive for future research for understanding how positioning and 3D orientation of primary cilia may be related to their hypothesized signaling roles within different cellular populations.
    Developmental Dynamics 11/2011; 240(11):2405-31. DOI:10.1002/dvdy.22756 · 2.38 Impact Factor
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