Genetic Elimination of Suppressor of Fused Reveals an Essential Repressor Function in the Mammalian Hedgehog Signaling Pathway

Department of Biosciences at Novum, Karolinska Institutet, SE-141 57 Huddinge, Sweden.
Developmental Cell (Impact Factor: 9.71). 03/2006; 10(2):187-97. DOI: 10.1016/j.devcel.2005.12.013
Source: PubMed


The Hedgehog (Hh) pathway plays important roles during embryogenesis and carcinogenesis. Here, we show that ablation of the mouse Suppressor of fused (Sufu), an intracellular pathway component, leads to embryonic lethality at approximately E9.5 with cephalic and neural tube defects. Fibroblasts derived from Sufu(-/-) embryos showed high Gli-mediated Hh pathway activity that could not be modulated at the level of Smoothened and could only partially be blocked by PKA activation. Despite the robust constitutive pathway activation in the Sufu(-/-) fibroblasts, the GLI1 steady-state localization remained largely cytoplasmic, implying the presence of an effective nuclear export mechanism. Sufu(+/-) mice develop a skin phenotype with basaloid changes and jaw keratocysts, characteristic features of Gorlin syndrome, a human genetic disease linked to enhanced Hh signaling. Our data demonstrate that, in striking contrast to Drosophila, in mammals, Sufu has a central role, and its loss of function leads to potent ligand-independent activation of the Hh pathway.

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    • "Suppressor of Fused (Sufu) is a cytoplasmic protein with critical roles in mammalian development. Sufu knockout mice fail to survive past embryonic day 9.5 (E9.5), indicating an essential role in early mammalian development (Cooper et al., 2005; Svä rd et al., 2006). At later stages, Sufu plays an important role in the development of specific CNS structures. "
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    ABSTRACT: Proper lineage progression and diversification of neural progenitor cells (NPCs) ensures the generation of projection neuron (PN) subtypes in the mammalian neocortex. Here, we show that Suppressor of Fused (Sufu) controls PN specification by maintaining the identity of NPCs in the embryonic neocortex. Deletion of Sufu in NPCs of the E10.5 mouse neocortex led to improper specification of progenitors and a reduction in intermediate progenitors (IPs) during corticogenesis. We found that Sufu deletion resulted in unstable Gli2 and Gli3 activity, leading to the ectopic activation of Sonic hedgehog (Shh) signaling. The role of Sufu in maintaining progenitor identity is critical at early stages of corticogenesis, since deletion of Sufu at E13.5 did not cause similar abnormalities. Our studies revealed that Sufu critically modulates Shh signaling at early stages of neurogenesis for proper specification and maintenance of cortical NPCs to ensure the appropriate generation of cortical PN lineages.
    Cell Reports 09/2015; 12(12). DOI:10.1016/j.celrep.2015.08.031 · 8.36 Impact Factor
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    • "In addition, it has been reported that mammalian Sufu directly modulates the transcriptional activity of Gli in the nucleus through recruitment of a corepressor complex (Cheng and Bishop, 2002; Paces-Fessy et al., 2004). The absence of Sufu results in constitutive Hh pathway activation similar to loss of Ptch1 in mouse but has no effect in Drosophila (Préat 1992; Cooper et al., 2005; Svärd et al., 2006). The differences in these phenotypes indicate that Sufu is the major inhibitor of Gli activity in mammals downstream of Ptch1, while multiple inhibitory mechanisms exist in flies (Jiang and Hui, 2008). "
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    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
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    • "To further prove that GlaB is acting downstream of Smo, we used SuFu À/À MEFs. Reporter activity in these cells is high even in the absence of Shh or Smo stimulation, because of the loss of the well-known Gli1 inhibitor SuFu (Fig 2E), and is not suppressed by treatment with the Smo inhibitor cyclopamine (Svard et al, 2006). In this cellular context, GlaB reduced constitutive endogenous Hh target gene expression (Fig 2F). "
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    ABSTRACT: Hedgehog signaling is essential for tissue development and stemness, and its deregulation has been observed in many tumors. Aberrant activation of Hedgehog signaling is the result of genetic mutations of pathway components or other Smo-dependent or independent mechanisms, all triggering the downstream effector Gli1. For this reason, understanding the poorly elucidated mechanism of Gli1-mediated transcription allows to identify novel molecules blocking the pathway at a downstream level, representing a critical goal in tumor biology. Here, we clarify the structural requirements of the pathway effector Gli1 for binding to DNA and identify Glabrescione B as the first small molecule binding to Gli1 zinc finger and impairing Gli1 activity by interfering with its interaction with DNA. Remarkably, as a consequence of its robust inhibitory effect on Gli1 activity, Glabrescione B inhibited the growth of Hedgehog-dependent tumor cells in vitro and in vivo as well as the self-renewal ability and clonogenicity of tumor-derived stem cells. The identification of the structural requirements of Gli1/DNA interaction highlights their relevance for pharmacologic interference of Gli signaling.
    The EMBO Journal 12/2014; 34(2). DOI:10.15252/embj.201489213 · 10.43 Impact Factor
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