Novel genes regulated by Sonic Hedgehog in pluripotent mesenchymal cells.
Sonic Hedgehog is a secreted morphogen involved in patterning a wide range of structures in the developing embryo. Disruption of the Hedgehog signalling cascade leads to a number of developmental disorders and plays a key role in the formation of a range of human cancers. The identification of genes regulated by Hedgehog is crucial to understanding how disruption of this pathway leads to neoplastic transformation. We have used a Sonic Hedgehog (Shh) responsive mouse cell line, C3H/10T1/2, to provide a model system for hedgehog target gene discovery. Following activation of cell cultures with Shh, RNA was used to interrogate microarrays to investigate downstream transcriptional consequences of hedgehog stimulation. As a result 11 target genes have been identified, seven of which are induced (Thrombomodulin, GILZ, BF-2, Nr4a1, IGF2, PMP22, LASP1) and four of which are repressed (SFRP-1, SFRP-2, Mip1-gamma, Amh) by Shh. These targets have a diverse range of putative functions and include transcriptional regulators and molecules known to be involved in regulating cell growth or apoptosis. The corroboration of genes previously implicated in hedgehog signalling, along with the finding of novel targets, demonstrates both the validity and power of the C3H/10T1/2 system for Shh target gene discovery.
Ingram
Wendy J
WJ
Institute for Molecular Bioscience and Department of Biochemistry and Molecular Biology, The University of Queensland, Queensland 4072, Australia.
Wicking
Carol A
CA
Grimmond
Sean M
SM
Forrest
Alistair R
AR
Wainwright
Brandon J
BJ
D000818:Animals; D054304:Anti-Mullerian Hormone; D002452:Cell Count; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000235:genetics; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000096:biosynthesis / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D008648:Mesoderm / Q000166:cytology*; D051379:Mice; D008809:Mice, Inbred C3H; D009185:Myelin Proteins / Q000096:biosynthesis / Q000235:genetics; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D020411:Oligonucleotide Array Sequence Analysis; D039904:Pluripotent Stem Cells / Q000378:metabolism*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins / Q000502:physiology; D015398:Signal Transduction; D013735:Testicular Hormones / Q000096:biosynthesis / Q000235:genetics; D018180:Thrombomodulin / Q000096:biosynthesis / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D014162:Transfection; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D054304:Anti-Mullerian Hormone; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; D006023:Glycoproteins; D006131:Growth Inhibitors; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D007335:Insulin-Like Growth Factor II; D047908:Intracellular Signaling Peptides and Proteins; D060588:LIM Domain Proteins; D008565:Membrane Proteins; D009185:Myelin Proteins; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D057105:Nuclear Receptor Subfamily 4, Group A, Member 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D013735:Testicular Hormones; D018180:Thrombomodulin; D015534:Trans-Activators; D014157:Transcription Factors; D000099274:Frizzled-Related Proteins; C498608:Dsip1 protein, mouse; C489562:Foxd1 protein, mouse; C490692:Lasp1 protein, mouse; C539821:NR4A1 protein, human; C539818:Nr4a1 protein, mouse; C539820:Nr4a1 protein, rat; C489545:Pmp22 protein, mouse; C489546:Pmp22 protein, rat; C491628:Sfrp2 protein, mouse; D000094742:Secreted Frizzled-Related Proteins; C465570:Shh protein, mouse