Genetic Elimination of Suppressor of Fused Reveals an Essential Repressor Function in the Mammalian Hedgehog Signaling Pathway
| Autor: | Jessica, Svärd, Karin, Heby-Henricson, Karin Heby, Henricson, Madelen, Persson-Lek, Björn, Rozell, Matthias, Lauth, Asa, Bergström, Johan, Ericson, Rune, Toftgård, Stephan, Teglund |
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| Rok vydání: | 2006 |
| Předmět: |
Neural tube patterning
DEVBIO Nervous System Receptors G-Protein-Coupled Mice 0302 clinical medicine Pregnancy Skin Mice Knockout Genetics 0303 health sciences biology Intracellular Signaling Peptides and Proteins Gene Expression Regulation Developmental Basal Cell Nevus Syndrome Smoothened Receptor Hedgehog signaling pathway Cell biology Phenotype SIGNALING 030220 oncology & carcinogenesis Female Signal transduction Signal Transduction Patched Receptors Recombinant Fusion Proteins Green Fluorescent Proteins Kruppel-Like Transcription Factors Embryonic Development Receptors Cell Surface Zinc Finger Protein GLI1 General Biochemistry Genetics and Molecular Biology 03 medical and health sciences GLI1 Animals Humans Hedgehog Proteins Molecular Biology Hedgehog 030304 developmental biology Membrane Proteins Cell Biology Fibroblasts Cyclic AMP-Dependent Protein Kinases Mice Mutant Strains Repressor Proteins Disease Models Animal Trans-Activators biology.protein Smoothened Developmental Biology |
| Zdroj: | Developmental Cell. 10:187-197 |
| ISSN: | 1534-5807 |
| DOI: | 10.1016/j.devcel.2005.12.013 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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