Tenzen T, Allen BL, Cole F, Kang JS, Krauss RS, McMahon APThe cell surface membrane protein Cdo and Boc are components and targets of the Hedgehog signaling pathway and feedback network in mice. Dev Cell 10: 647-656

Department of Molecular and Cellular Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts 02138, USA.
Developmental Cell (Impact Factor: 9.71). 06/2006; 10(5):647-56. DOI: 10.1016/j.devcel.2006.04.004
Source: PubMed


Cdo and Boc encode cell surface Ig/fibronectin superfamily members linked to muscle differentiation. Data here indicate they are also targets and signaling components of the Sonic hedgehog (Shh) pathway. Although Cdo and Boc are generally negatively regulated by Hedgehog (HH) signaling, in the neural tube Cdo is expressed within the Shh-dependent floor plate while Boc expression lies within the dorsal limit of Shh signaling. Loss of Cdo results in a Shh dosage-dependent reduction of the floor plate. In contrast, ectopic expression of Boc or Cdo results in a Shh-dependent, cell autonomous promotion of ventral cell fates and a non-cell-autonomous ventral expansion of dorsal cell identities consistent with Shh sequestration. Cdo and Boc bind Shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where Cdo and Boc enhance Shh signaling within its target field.

Download full-text


Available from: Francesca Cole, Jul 27, 2015
  • Source
    • "Boc in vertebrates) (McLellan et al., 2006; Okada et al., 2006; Tenzen et al., 2006; Yao et al., 2006; Zhang et al., 2006b; Zheng et al., 2010; Allen et al., 2011; Izzi et al., 2011). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The Hedgehog (Hh) signaling pathway plays crucial roles both in embryonic development and in adult stem cell function. The timing, duration and location of Hh signaling activity need to be tightly controlled. Abnormalities of Hh signal transduction lead to birth defects or malignant tumors. Recent data point to ubiquitination-related posttranslational modifications of several key Hh pathway components as an important mechanism of regulation of the Hh pathway. Here we review how ubiquitination regulates the localization, stability and activity of the key Hh signaling components.
    06/2015; 10(3). DOI:10.1007/s11515-015-1343-5
  • Source
    • "As the expression of this gene in the lens appears to be restricted to the lens placode and early lens vesicle stages (E10.5–E12.5) [56] and is known to enhance Shh signaling [57], it is plausible that the transient expression of this co-receptor at these stages underlies the transient activity of the Hh pathway in the lens, documented here. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Various studies suggest that Hedgehog (Hh) signalling plays roles in human and zebrafish ocular development. Recent studies (Kerr et al., Invest Ophthalmol Vis Sci. 2012; 53, 3316-30) showed that conditionally activating Hh signals promotes murine lens epithelial cell proliferation and disrupts fibre differentiation. In this study we examined the expression of the Hh pathway and the requirement for the Smoothened gene in murine lens development. Expression of Hh pathway components in developing lens was examined by RT-PCR, immunofluorescence and in situ hybridisation. The requirement of Smo in lens development was determined by conditional loss-of-function mutations, using LeCre and MLR10 Cre transgenic mice. The phenotype of mutant mice was examined by immunofluorescence for various markers of cell cycle, lens and cornea differentiation. Hh pathway components (Ptch1, Smo, Gli2, Gli3) were detected in lens epithelium from E12.5. Gli2 was particularly localised to mitotic nuclei and, at E13.5, Gli3 exhibited a shift from cytosol to nucleus, suggesting distinct roles for these transcription factors. Conditional deletion of Smo, from ∼E12.5 (MLR10 Cre) did not affect ocular development, whereas deletion from ∼E9.5 (LeCre) resulted in lens and corneal defects from E14.5. Mutant lenses were smaller and showed normal expression of p57Kip2, c-Maf, E-cadherin and Pax6, reduced expression of FoxE3 and Ptch1 and decreased nuclear Hes1. There was normal G1-S phase but decreased G2-M phase transition at E16.5 and epithelial cell death from E14.5-E16.5. Mutant corneas were thicker due to aberrant migration of Nrp2+ cells from the extraocular mesenchyme, resulting in delayed corneal endothelial but normal epithelial differentiation. These results indicate the Hh pathway is required during a discrete period (E9.5-E12.5) in lens development to regulate lens epithelial cell proliferation, survival and FoxE3 expression. Defective corneal development occurs secondary to defects in lens and appears to be due to defective migration of peri-ocular Nrp2+ neural crest/mesenchymal cells.
    PLoS ONE 09/2014; 9(9):e108037. DOI:10.1371/journal.pone.0108037 · 3.23 Impact Factor
  • Source
    • "We recently identified that in addition to the Shh receptor Ptch1, at least one coreceptor (Boc, Cdon, or Gas1) is required to form a functional Shh reception complex with Ptch1 and mediate Shh signaling (Allen et al., 2011; Izzi et al., 2011). These coreceptors have overlapping but distinct expression patterns, explaining their redundant role in some tissues but not others (Allen et al., 2011; Izzi et al., 2011; Okada et al., 2006; Tenzen et al., 2006; Zhang et al., 2006). Maintained or overactivation of the Shh signaling pathway can lead to cancer. "
    [Show abstract] [Hide abstract]
    ABSTRACT: During cerebellar development, Sonic hedgehog (Shh) signaling drives the proliferation of granule cell precursors (GCPs). Aberrant activation of Shh signaling causes overproliferation of GCPs, leading to medulloblastoma. Although the Shh-binding protein Boc associates with the Shh receptor Ptch1 to mediate Shh signaling, whether Boc plays a role in medulloblastoma is unknown. Here, we show that BOC is upregulated in medulloblastomas and induces GCP proliferation. Conversely, Boc inactivation reduces proliferation and progression of early medulloblastomas to advanced tumors. Mechanistically, we find that Boc, through elevated Shh signaling, promotes high levels of DNA damage, an effect mediated by CyclinD1. High DNA damage in the presence of Boc increases the incidence of Ptch1 loss of heterozygosity, an important event in the progression from early to advanced medulloblastoma. Together, our results indicate that DNA damage promoted by Boc leads to the demise of its own coreceptor, Ptch1, and consequently medulloblastoma progression.
    Developmental Cell 09/2014; 31(1). DOI:10.1016/j.devcel.2014.08.010 · 9.71 Impact Factor
Show more