The Eya1 Phosphatase Promotes Shh Signaling during Hindbrain Development and Oncogenesis

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.

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The Eya1 Phosphatase Promotes Shh Signaling during Hindbrain Development and Oncogenesis

Published Date:

Mar 26 2015

Publisher's site:

http://dx.doi.org/ New Site Icon

Source:

Dev Cell. 2015; 33(1):22-35.

[PDF-2.13 MB]

Details:

Personal Authors:

Eisner, Adriana ; Pazyra-Murphy, Maria ; Durresi, Ershela ; Zhou, Pengcheng ; Zhao, Xuesong ; ... More ▼

Keywords:

[+]

Pubmed ID:

25816987

Pubmed Central ID:

PMC4418443

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.

Document Type:

Journal Article

Collection(s):

CDC Public Access

Funding:

CA142536/CA/NCI NIH HHS/United States
DP1000839/DP/NCCDPHP CDC HHS/United States
NIH NS045500/NS/NINDS NIH HHS/United States
NIH R01 DK64640/DK/NIDDK NIH HHS/United States
P01 CA142536/CA/NCI NIH HHS/United States
R01 DC005824/DC/NIDCD NIH HHS/United States
R01 NS045500/NS/NINDS NIH HHS/United States
T32 CA009361/CA/NCI NIH HHS/United States
T32 GM007753/GM/NIGMS NIH HHS/United States
T32CA009361/CA/NCI NIH HHS/United States

Supporting Files:

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