Shh controls epithelial proliferation via independent pathways that converge on N-Myc.
Shh signaling induces proliferation of many cell types during development and disease, but how Gli transcription factors regulate these mitogenic responses remains unclear. By genetically altering levels of Gli activator and repressor functions in mice, we have demonstrated that both Gli functions are involved in the transcriptional control of N-myc and Cyclin D2 during embryonic hair follicle development. Our results also indicate that additional Gli-activator-dependent functions are required for robust mitogenic responses in regions of high Shh signaling. Through posttranscriptional mechanisms, including inhibition of GSK3-beta activity, Shh signaling leads to spatially restricted accumulation of N-myc and coordinated cell cycle progression. Furthermore, a temporal shift in the regulation of GSK3-beta activity occurs during embryonic hair follicle development, resulting in a synergy with beta-catenin signaling to promote coordinated proliferation. These findings demonstrate that Shh signaling controls the rapid and patterned expansion of epithelial progenitors through convergent Gli-mediated regulation.
Mill
Pleasantine
P
Department of Medical and Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1X8, Canada.
Mo
Rong
R
Hu
Ming Chang
MC
Dagnino
Lina
L
Rosenblum
Norman D
ND
Hui
Chi-Chung
CC
D000818:Animals; D049109:Cell Proliferation; D056742:Cyclin D2; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000078404:Epidermal Cells; D004817:Epidermis / Q000196:embryology / Q000502:physiology*; D004847:Epithelial Cells / Q000502:physiology*; D016193:G1 Phase; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D018859:Hair Follicle / Q000196:embryology / Q000502:physiology; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic; D000074290:Zinc Finger Protein Gli3; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D016213:Cyclins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D016271:Proto-Oncogene Proteins c-myc; C465570:Shh protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D000074290:Zinc Finger Protein Gli3; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3