Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells

Hae Young Lee, James M Angelastro, Anna Marie Kenney, Carol A. Mason, Lloyd A. Greene

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Precise regulation of neuroprogenitor cell proliferation and differentiation is required for successful brain development, but the factors that contribute to this are only incompletely understood. The transcription factor ATF5 promotes proliferation of cerebral cortical neuroprogenitor cells and its down regulation permits their differentiation. Here, we examine the expression and regulation of ATF5 in cerebellar granule neuron progenitor cells (CGNPs) as well as the role of ATF5 in the transition of CGNPs to postmitotic cerebellar granule neurons (GCNs). We find that ATF5 is expressed by proliferating CGNPs in both the embryonic and postnatal cerebellar external granule layer (EGL) and in the rhombic lip, the embryonic structure from which the EGL arises. In contrast, ATF5 is undetectable in postmitotic GCNs. In highly enriched dissociated cultures of CGNPs and CGNs, ATF5 is expressed only in CGNPs. Constitutive ATF5 expression in CGNPs does not affect their proliferation or exit from the cell cycle. In contrast, in presence of sonic hedgehog (Shh), a mitogen for CGNPs, constitutively expressed ATF5 promotes CGNP proliferation and delays their cell cycle exit and differentiation. Conversely, ATF5 loss-of-function conferred by a dominant-negative form of ATF5 significantly diminishes Shh-stimulated CGNP proliferation and promotes differentiation. In parallel with its stimulation of CGNP proliferation, Shh enhances ATF5 expression by what appeared to be a posttranscriptional mechanism involving protein stabilization. These findings indicate a reciprocal interaction between ATF5 and Shh in which Shh stimulates ATF5 expression and in which ATF5 contributes to Shh-stimulated CGNP expansion.

Original languageEnglish (US)
Pages (from-to)789-804
Number of pages16
JournalDevelopmental Neurobiology
Volume72
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Stem Cells
Neurons
Cell Proliferation
Cell Differentiation
Cell Cycle
Lip
Mitogens
Transcription Factors
Down-Regulation
Embryonic Structures
Brain

Keywords

  • ATF5
  • Cerebellar granule neuron progenitor cells
  • Cerebellar granule neurons
  • Cerebellum
  • External granule layer
  • Sonic hedgehog

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Developmental Neuroscience

Cite this

Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells. / Lee, Hae Young; Angelastro, James M; Kenney, Anna Marie; Mason, Carol A.; Greene, Lloyd A.

In: Developmental Neurobiology, Vol. 72, No. 6, 06.2012, p. 789-804.

Research output: Contribution to journalArticle

Lee, Hae Young ; Angelastro, James M ; Kenney, Anna Marie ; Mason, Carol A. ; Greene, Lloyd A. / Reciprocal actions of ATF5 and Shh in proliferation of cerebellar granule neuron progenitor cells. In: Developmental Neurobiology. 2012 ; Vol. 72, No. 6. pp. 789-804.
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