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

• Published in: Developmental cell 2006-02, Vol.10 (2), p.187-197
• Main Authors: Svärd, Jessica, Henricson, Karin Heby, Persson-Lek, Madelen, Rozell, Björn, Lauth, Matthias, Bergström, Åsa, Ericson, Johan, Toftgård, Rune, Teglund, Stephan
• Format: Article
• Language: English
• Subjects: Animals; Basal Cell Nevus Syndrome - genetics; Basal Cell Nevus Syndrome - metabolism; Basal Cell Nevus Syndrome - pathology; Biological and medical sciences; Cell differentiation, maturation, development, hematopoiesis; Cell physiology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; DEVBIO; Disease Models, Animal; Embryonic Development - genetics; Female; Fibroblasts - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Hedgehog Proteins; Humans; Intracellular Signaling Peptides and Proteins - deficiency; Intracellular Signaling Peptides and Proteins - genetics; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Medicin och hälsovetenskap; Membrane Proteins - deficiency; Membrane Proteins - genetics; Mice; Mice, Knockout; Mice, Mutant Strains; Molecular and cellular biology; Nervous System - embryology; Patched Receptors; Phenotype; Pregnancy; Receptors, Cell Surface; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - antagonists & inhibitors; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction; SIGNALING; Skin - metabolism; Skin - pathology; Smoothened Receptor; Trans-Activators - metabolism; Zinc Finger Protein GLI1
• ISSN: 1534-5807; 1878-1551
• DOI: 10.1016/j.devcel.2005.12.013

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 ∼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.