The Eya1 Phosphatase Promotes Shh Signaling during Hindbrain Development and Oncogenesis

Details

• Alternative Title:
  Dev Cell
• Personal Author:
  Eisner, Adriana ; Pazyra-Murphy, Maria ; Durresi, Ershela ; Zhou, Pengcheng ; Zhao, Xuesong ; Chadwick, Emily C. ; Xu, Pin-Xian ; Hillman, R. Tyler ; Scott, Matthew P. ; Greenberg, Michael E. ; Segal, Rosalind A.
• Description:
  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.
• Subjects:
  Animals Biomarkers, Tumor Blotting, Western Carcinogenesis Cells, Cultured Chromatin Immunoprecipitation Gene Expression Profiling Hedgehog Proteins Homeodomain Proteins Humans Immunoenzyme Techniques Immunoprecipitation Intracellular Signaling Peptides And Proteins Kruppel-Like Transcription Factors Medulloblastoma Mice Mice, Knockout Mutation Nuclear Proteins Oligonucleotide Array Sequence Analysis Patched Receptors Protein Tyrosine Phosphatases Real-Time Polymerase Chain Reaction Receptors, Cell Surface Reverse Transcriptase Polymerase Chain Reaction Rhombencephalon RNA, Messenger RNA, Small Interfering Signal Transduction Zinc Finger Protein GLI1

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• Source:
  Dev Cell. 2015; 33(1):22-35
• Pubmed ID:
  25816987
• Pubmed Central ID:
  PMC4418443
• Document Type:
  Journal Article
• Funding:
  R01 DC014718/DC/NIDCD NIH HHSUnited States/ ; NIH NS045500/NS/NINDS NIH HHSUnited States/ ; T32CA009361/CA/NCI NIH HHSUnited States/ ; T32 GM007753/GM/NIGMS NIH HHSUnited States/ ; NIH R01 DK64640/DK/NIDDK NIH HHSUnited States/ ; R01 NS045500/NS/NINDS NIH HHSUnited States/ ; R01 DC005824/DC/NIDCD NIH HHSUnited States/ ; DP1000839/DP/NCCDPHP CDC HHSUnited States/ ; R01 DK064640/DK/NIDDK NIH HHSUnited States/ ; T32 CA009361/CA/NCI NIH HHSUnited States/ ; P01 CA142536/CA/NCI NIH HHSUnited States/ ; CA142536/CA/NCI NIH HHSUnited States/
• Volume:
  33
• Issue:
  1
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:7defee3809177bc604b0ca3a761a2bcd412b781e00f0d54f9a4f4666e8933f49
• Download URL:
  https://stacks.cdc.gov/view/cdc/31385/cdc_31385_DS1.pdf
• File Type:
  [PDF - 2.13 MB ]