title: Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway.
abstract: 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.
authors.affiliation: Department of Biosciences at Novum, Karolinska Institutet, SE-141 57 Huddinge, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Svärd
authors.forename: Karin
authors.initials: K
authors.lastname: Heby-Henricson
authors.forename: Karin Heby
authors.initials: KH
authors.lastname: Henricson
authors.forename: Madelen
authors.initials: M
authors.lastname: Persson-Lek
authors.forename: Björn
authors.initials: B
authors.lastname: Rozell
authors.forename: Matthias
authors.initials: M
authors.lastname: Lauth
authors.forename: Asa
authors.initials: A
authors.lastname: Bergström
authors.forename: Johan
authors.initials: J
authors.lastname: Ericson
authors.forename: Rune
authors.initials: R
authors.lastname: Toftgård
authors.forename: Stephan
authors.initials: S
authors.lastname: Teglund
mesh_terms: D000818:Animals; D001478:Basal Cell Nevus Syndrome / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004195:Disease Models, Animal; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D053823:Hedgehog Proteins; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D009420:Nervous System / Q000196:embryology; D000072079:Patched Receptors; D010641:Phenotype; D011247:Pregnancy; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000037:antagonists & inhibitors; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D000072086:Smoothened Receptor; D015534:Trans-Activators / Q000378:metabolism*; D000071676:Zinc Finger Protein GLI1
chemical_list: C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D008565:Membrane Proteins; D000072079:Patched Receptors; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; C490763:Sufu protein, mouse; D015534:Trans-Activators; D000071676:Zinc Finger Protein GLI1; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D017868:Cyclic AMP-Dependent Protein Kinases