The Eya1 phosphatase promotes shh signaling during hindbrain development and oncogenesis

Adriana Eisner; Maria F. Pazyra-Murphy; Ershela Durresi; Pengcheng Zhou; Xuesong Zhao; Emily C. Chadwick; Pin Xian Xu; R. Tyler Hillman; Matthew P. Scott; Michael E. Greenberg; Rosalind A. Segal

doi:10.1016/j.devcel.2015.01.033

The Eya1 phosphatase promotes shh signaling during hindbrain development and oncogenesis

Adriana Eisner, Maria F. Pazyra-Murphy, Ershela Durresi, Pengcheng Zhou, Xuesong Zhao, Emily C. Chadwick, Pin Xian Xu, R. Tyler Hillman, Matthew P. Scott, Michael E. Greenberg, Rosalind A. Segal

Research output: Contribution to journal › Article › peer-review

27 Scopus citations

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.

Original language	English
Pages (from-to)	22-35
Number of pages	14
Journal	Developmental Cell
Volume	33
Issue number	1
DOIs	https://doi.org/10.1016/j.devcel.2015.01.033
State	Published - 6 Apr 2015

Access to Document

10.1016/j.devcel.2015.01.033

Cite this

@article{320ea902ea42418eb83ead14c41f2d07,

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.",

author = "Adriana Eisner and Pazyra-Murphy, {Maria F.} and Ershela Durresi and Pengcheng Zhou and Xuesong Zhao and Chadwick, {Emily C.} and Xu, {Pin Xian} and Hillman, {R. Tyler} and Scott, {Matthew P.} and Greenberg, {Michael E.} and Segal, {Rosalind A.}",

note = "Funding Information: We thank William Hahn, So Young Kim, and the Broad Institute RNAi Consortium for help with the shRNA screen and Alexandra Smolyanskaya for help with analyzing the screen. We thank Lisa Goodrich, Clifford Tabin for providing probes for in situ hybridization studies, and Richard Pestell for the Eya1 WT and Eya1 D237A constructs in pCDF. We thank members of the Segal laboratory for help and advice. These studies were supported by grants from the NIH: T32CA009361 (A.E., R.A.S.), Director{\textquoteright}s Pioneer Award DP1000839 (R.A.S.), CA142536 (R.A.S.) and support from the PLGA Foundation; NIH R01 DK64640 (P.-X.X.); NIH NS045500 (M.E.G.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = apr,

day = "6",

doi = "10.1016/j.devcel.2015.01.033",

language = "English",

volume = "33",

pages = "22--35",

journal = "Developmental Cell",

issn = "1534-5807",

publisher = "Cell Press",

number = "1",

}

TY - JOUR

T1 - The Eya1 phosphatase promotes shh signaling during hindbrain development and oncogenesis

AU - Eisner, Adriana

AU - Pazyra-Murphy, Maria F.

AU - Durresi, Ershela

AU - Zhou, Pengcheng

AU - Zhao, Xuesong

AU - Chadwick, Emily C.

AU - Xu, Pin Xian

AU - Hillman, R. Tyler

AU - Scott, Matthew P.

AU - Greenberg, Michael E.

AU - Segal, Rosalind A.

N1 - Funding Information: We thank William Hahn, So Young Kim, and the Broad Institute RNAi Consortium for help with the shRNA screen and Alexandra Smolyanskaya for help with analyzing the screen. We thank Lisa Goodrich, Clifford Tabin for providing probes for in situ hybridization studies, and Richard Pestell for the Eya1 WT and Eya1 D237A constructs in pCDF. We thank members of the Segal laboratory for help and advice. These studies were supported by grants from the NIH: T32CA009361 (A.E., R.A.S.), Director’s Pioneer Award DP1000839 (R.A.S.), CA142536 (R.A.S.) and support from the PLGA Foundation; NIH R01 DK64640 (P.-X.X.); NIH NS045500 (M.E.G.). Publisher Copyright: © 2015 Elsevier Inc.

PY - 2015/4/6

Y1 - 2015/4/6

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84926407491&partnerID=8YFLogxK

U2 - 10.1016/j.devcel.2015.01.033

DO - 10.1016/j.devcel.2015.01.033

M3 - Article

C2 - 25816987

AN - SCOPUS:84926407491

SN - 1534-5807

VL - 33

SP - 22

EP - 35

JO - Developmental Cell

JF - Developmental Cell

IS - 1

ER -

The Eya1 phosphatase promotes shh signaling during hindbrain development and oncogenesis

Abstract

Access to Document

Fingerprint

Cite this