title: The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis.
abstract: Sonic hedgehog (Shh) signaling is critical in development and oncogenesis, but the mechanisms regulating this pathway remain unclear. Although protein phosphorylation clearly affects Shh signaling, little is known about phosphatases governing the pathway. Here, we conducted a small hairpin RNA (shRNA) screen of the phosphatome and identified Eya1 as a positive regulator of Shh signaling. We find that the catalytically active phosphatase Eya1 cooperates with the DNA-binding protein Six1 to promote gene induction in response to Shh and that Eya1/Six1 together regulate Gli transcriptional activators. We show that Eya1, which is mutated in a human deafness disorder, branchio-oto-renal syndrome, is critical for Shh-dependent hindbrain growth and development. Moreover, Eya1 drives the growth of medulloblastoma, a Shh-dependent hindbrain tumor. Together, these results identify Eya1 and Six1 as key components of the Shh transcriptional network in normal development and in oncogenesis.
authors: Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Adriana
authors: A
authors: Eisner
authors: Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Maria F
authors: MF
authors: Pazyra-Murphy
authors: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Ershela
authors: E
authors: Durresi
authors: Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Pengcheng
authors: P
authors: Zhou
authors: Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Xuesong
authors: X
authors: Zhao
authors: Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Emily C
authors: EC
authors: Chadwick
authors: Department of Genetics and Genomic Sciences, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
authors: Pin-Xian
authors: PX
authors: Xu
authors: Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305-5439, USA.
authors: R Tyler
authors: RT
authors: Hillman
authors: Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305-5439, USA.
authors: Matthew P
authors: MP
authors: Scott
authors: Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
authors: Michael E
authors: ME
authors: Greenberg
authors: Departments of Cancer Biology and Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: rosalind_segal@dfci.harvard.edu.
authors: Rosalind A
authors: RA
authors: Segal
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D020869:Gene Expression Profiling; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology*; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D000072079:Patched Receptors; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012249:Rhombencephalon / Q000166:cytology* / Q000378:metabolism; D015398:Signal Transduction; D000071676:Zinc Finger Protein GLI1
chemical_list: D014408:Biomarkers, Tumor; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D018398:Homeodomain Proteins; D047908:Intracellular Signaling Peptides and Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D000072079:Patched Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; C465570:Shh protein, mouse; C490947:Six1 protein, mouse; D000071676:Zinc Finger Protein GLI1; C501156:Eya1 protein, mouse; D017027:Protein Tyrosine Phosphatases