Sall1, a causative gene for Townes-Brocks syndrome, enhances the canonical Wnt signaling by localizing to heterochromatin.
The Spalt (sal) gene family plays an important role in regulating developmental processes of many organisms. Mutations of human SALL1 cause the autosomal dominant disorder, Townes-Brocks syndrome (TBS), and result in ear, limb, anal, renal, and heart anomalies. Targeted deletion of mouse Sall1 results in kidney agenesis or severe dysgenesis. Molecular mechanisms of Sall1, however, have remained largely unknown. Here we report that Sall1 synergistically activates canonical Wnt signaling. The transcriptional activity of Sall1 is related to its nuclear localization to punctate nuclear foci (pericentromeric heterochromatin), but not to its localization or association with beta-catenin, the nuclear component of Wnt signaling. In contrast, the RNA interference of Sall1 reduces reporter activities of canonical Wnt signaling. The N-terminal truncated Sall1, produced by mutations often found in TBS, disturbs localization of native Sall1 to heterochromatin, and also down-regulates the synergistic transcriptional enhancement for Wnt signal by native Sall1. Thus, we propose a new mechanism for Wnt signaling activation, that is the heterochromatin localization of Sall1.
Sato
Akira
A
Department of Stem Cell Regulation, The Institute of Medical Science, The University of Tokyo, Japan.
Kishida
Shosei
S
Tanaka
Toshiya
T
Kikuchi
Akira
A
Kodama
Tatsuhiko
T
Asashima
Makoto
M
Nishinakamura
Ryuichi
R
D000818:Animals; D000911:Antibodies, Monoclonal / Q000737:chemistry; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016895:Culture Media, Serum-Free / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000737:chemistry / Q000378:metabolism; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D005799:Genes, Dominant; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins; D006570:Heterochromatin / Q000737:chemistry*; D006801:Humans; D007150:Immunohistochemistry; D008164:Luminescent Proteins / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D013577:Syndrome; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D016335:Zinc Fingers; D051176:beta Catenin
D000911:Antibodies, Monoclonal; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D018076:DNA, Complementary; D006570:Heterochromatin; D008164:Luminescent Proteins; D011518:Proto-Oncogene Proteins; C104146:SALL1 protein, human; C491254:Sall1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D049452:Green Fluorescent Proteins