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Mutations in CDON, Encoding a Hedgehog Receptor, Result in Holoprosencephaly and Defective Interactions with Other Hedgehog Receptors

Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, NY 10029, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 08/2011; 89(2):231-40. DOI: 10.1016/j.ajhg.2011.07.001
Source: PubMed

ABSTRACT Holoprosencephaly (HPE), a common human congenital anomaly defined by a failure to delineate the midline of the forebrain and/or midface, is associated with diminished Sonic hedgehog (SHH)-pathway activity in development of these structures. SHH signaling is regulated by a network of ligand-binding factors, including the primary receptor PTCH1 and the putative coreceptors, CDON (also called CDO), BOC, and GAS1. Although binding of SHH to these receptors promotes pathway activity, it is not known whether interactions between these receptors are important. We report here identification of missense CDON mutations in human HPE. These mutations diminish CDON's ability to support SHH-dependent gene expression in cell-based signaling assays. The mutations occur outside the SHH-binding domain of CDON, and the encoded variant CDON proteins do not display defects in binding to SHH. In contrast, wild-type CDON associates with PTCH1 and GAS1, but the variants do so inefficiently, in a manner that parallels their activity in cell-based assays. Our findings argue that CDON must associate with both ligand and other hedgehog-receptor components, particularly PTCH1, for signaling to occur and that disruption of the latter interactions is a mechanism of HPE.

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    • "In humans, most cases of HPE are sporadic, caused by chromosomal abnormalities or syndromic disorders and generally incompatible with life (Kauvar and Muenke, 2010). Those individuals that do survive generally have non-syndromic HPE, with fourteen dominant loci currently identified in association with these forms, collectively encoding proteins functioning within four of the major molecular signaling pathways (Bone Morphogenetic Protein, Fibroblast Growth Factor, Nodal and Hedgehog) (Bae et al., 2011; Roessler and Muenke, 2010). However, environmental factors are also implicated in HPE and can include maternal diabetes, alcohol ingestion, cholesterollowering drugs and the steroidal alkaloid cyclopamine (Cohen, 1989; Cohen and Shiota, 2002). "
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    • "MEFs were derived from days 12.5–13.5 post coitus fetuses of strain ICR mice as previously described (Bae et al., 2011). "
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    ABSTRACT: Sonic hedgehog (Shh) signaling is required for numerous developmental processes including specification of ventral cell types in the central nervous system such as midbrain dopaminergic (DA) neurons. The multifunctional coreceptor Cdo increases the signaling activity of Shh which is crucial for development of forebrain and neural tube. In this study, we investigated the role of Cdo in midbrain DA neurogenesis. Cdo and Shh signaling components are induced during neurogenesis of embryonic stem (ES) cells. Cdo-/- ES cells show reduced neuronal differentiation accompanied by increased cell death upon neuronal induction. In addition, Cdo-/- ES cells form fewer tyrosine hydroxylase (TH) and microtubule associated protein 2 (MAP2)-positive DA neurons correlating with the decreased expression of key regulators of DA neurogenesis, such as Shh, Neurogenin2, Mash1, Foxa2, Lmx1a, Nurr1 and Pitx3, relative to the Cdo+/+ ES cells. Consistently, the Cdo-/- embryonic midbrain displays a reduction in expression of TH and Nurr1. Furthermore, activation of Shh signaling by treatment with Purmorphamine (Pur) restores the DA neurogenesis of Cdo-/- ES cells, suggesting that Cdo is required for the full Shh signaling activation to induce efficient DA neurogenesis.
    Stem Cell Research 09/2014; 13(2). DOI:10.1016/j.scr.2014.07.004 · 3.91 Impact Factor
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    • "In humans, most cases of HPE are sporadic, caused by chromosomal abnormalities or syndromic disorders and generally incompatible with life (Kauvar and Muenke, 2010). Those individuals that do survive generally have non-syndromic HPE, with fourteen dominant loci currently identified in association with these forms, collectively encoding proteins functioning within four of the major molecular signaling pathways (Bone Morphogenetic Protein, Fibroblast Growth Factor, Nodal and Hedgehog) (Bae et al., 2011; Roessler and Muenke, 2010). However, environmental factors are also implicated in HPE and can include maternal diabetes, alcohol ingestion, cholesterollowering drugs and the steroidal alkaloid cyclopamine (Cohen, 1989; Cohen and Shiota, 2002). "
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    ABSTRACT: Holoprosencephaly is a heterogeneous developmental malformation of the central nervous system characterized by impaired forebrain cleavage, midline facial anomalies and wide phenotypic variation. Indeed, microforms represent the mildest manifestation, associated with facial anomalies but an intact central nervous system. In many cases, perturbations in sonic hedgehog signaling are responsible for holoprosencephaly. Here, we have elucidated the contribution of Gas1 and an additional hedgehog co-receptor, Boc during early development of the craniofacial midline, by generating single and compound mutant mice. Significantly, we find Boc has an essential role in the etiology of a unique form of lobar holoprosencephaly that only occurs in conjunction with combined loss of Gas1. Whilst Gas1(-/-) mice have microform holoprosencephaly characterized by a single median maxillary central incisor, cleft palate and pituitary anomalies, Boc(-/-) mice have a normal facial midline. However, Gas1(-/-); Boc(-/-) mutants have lobar holoprosencephaly associated with clefting of the lip, palate and tongue, secondary to reduced sonic hedgehog transduction in the central nervous system and face. Moreover, maxillary incisor development is severely disrupted in these mice, arresting prior to cellular differentiation as a result of apoptosis in the odontogenic epithelium. Thus, Boc and Gas1 retain an essential function in these tooth germs, independent of their role in midline development of the central nervous system and face. Collectively, this phenotype demonstrates both redundancy and individual requirements for Gas1 and Boc during sonic hedgehog transduction in the craniofacial midline and suggests BOC as a potential digenic locus for lobar holoprosencephaly in human populations.
    Biology Open 07/2014; 3(8). DOI:10.1242/bio.20147989 · 2.42 Impact Factor
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