The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors

Daniel J. Merk, Pengcheng Zhou, Samuel M. Cohen, Maria F. Pazyra-Murphy, Grace H. Hwang, Kristina J. Rehm, Jose Alfaro, Christopher M. Reid, Xuesong Zhao, Eunyoung Park, Pin Xian Xu, Jennifer A. Chan, Michael J. Eck, Kellie J. Nazemi, Corey C. Harwell, Rosalind A. Segal

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants .

Original languageEnglish (US)
Pages (from-to)170-186
Number of pages17
JournalDevelopmental Neuroscience
Volume42
Issue number5-6
DOIs
StatePublished - Mar 2021

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

Fingerprint Dive into the research topics of 'The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors'. Together they form a unique fingerprint.

Cite this