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Dev Cell. 2015 Apr 6;33(1):22-35. doi: 10.1016/j.devcel.2015.01.033. Epub 2015 Mar 26.

The Eya1 phosphatase promotes Shh signaling during hindbrain development and oncogenesis.

Author information

1
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.
2
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
3
Department of Genetics and Genomic Sciences, Developmental and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY 10029-6574, USA.
4
Departments of Developmental Biology, Genetics, and Bioengineering, Stanford University School of Medicine, Stanford, CA 94305-5439, USA.
5
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.

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.

PMID:
25816987
PMCID:
PMC4418443
DOI:
10.1016/j.devcel.2015.01.033
[Indexed for MEDLINE]
Free PMC Article

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