Inhibition of Wnt signaling by Wise (Sostdc1) and negative feedback from Shh controls tooth number and patterning.
Mice carrying mutations in Wise (Sostdc1) display defects in many aspects of tooth development, including tooth number, size and cusp pattern. To understand the basis of these defects, we have investigated the pathways modulated by Wise in tooth development. We present evidence that, in tooth development, Wise suppresses survival of the diastema or incisor vestigial buds by serving as an inhibitor of Lrp5- and Lrp6-dependent Wnt signaling. Reducing the dosage of the Wnt co-receptor genes Lrp5 and Lrp6 rescues the Wise-null tooth phenotypes. Inactivation of Wise leads to elevated Wnt signaling and, as a consequence, vestigial tooth buds in the normally toothless diastema region display increased proliferation and continuous development to form supernumerary teeth. Conversely, gain-of-function studies show that ectopic Wise reduces Wnt signaling and tooth number. Our analyses demonstrate that the Fgf and Shh pathways are major downstream targets of Wise-regulated Wnt signaling. Furthermore, our experiments revealed that Shh acts as a negative-feedback regulator of Wnt signaling and thus determines the fate of the vestigial buds and later tooth patterning. These data provide insight into the mechanisms that control Wnt signaling in tooth development and into how crosstalk among signaling pathways controls tooth number and morphogenesis.
Ahn
Youngwook
Y
Stowers Institute for Medical Research, Kansas City, MO 64110, USA.
Sanderson
Brian W
BW
Klein
Ophir D
OD
Krumlauf
Robb
R
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D019521:Body Patterning; D019485:Bone Morphogenetic Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D051379:Mice; D008822:Mice, Transgenic; D015398:Signal Transduction; D014070:Tooth / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D019485:Bone Morphogenetic Proteins; D053823:Hedgehog Proteins; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; C555475:LRP6 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D060488:Low Density Lipoprotein Receptor-Related Protein-6; C555483:Lrp5 protein, mouse; C555476:Lrp6 protein, mouse; C465570:Shh protein, mouse; C483887:Sostdc1 protein, mouse; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors