Regulated Expression of ATF5 Is Required for the Progression of Neural Progenitor Cells to Neurons

Abstract

An important milestone in brain development is the transition of neuroprogenitor cells to postmitotic neurons. We report that the bZIP transcription factor ATF5 plays a major regulatory role in this process. In developing brain ATF5 expression is high within ventricular zones containing neural stem and progenitor cells and is undetectable in postmitotic neurons. In attached clonal neurosphere cultures ATF5 is expressed by neural stem/progenitor cells and is undetectable in tau-positive neurons. In PC12 cell cultures nerve growth factor (NGF) dramatically downregulates endogenous ATF5 protein and transcripts, whereas exogenous ATF5 suppresses NGF-promoted neurite outgrowth. Such inhibition requires the repression of CRE sites. In contrast, loss of function conferred by dominant-negative ATF5 accelerates NGF-promoted neuritogenesis. Exogenous ATF5 also suppresses, and dominant-negative ATF5 and a small-interfering RNA targeted to ATF5 promote, neurogenesis by cultured nestin-positive telencephalic cells. These findings indicate that ATF5 blocks the differentiation of neuroprogenitor cells into neurons and must be downregulated to permit this process to occur.

Selective destruction of glioblastoma cells by interference with the activity or expression of ATF5

“…Cells in the developing nervous system that expressed ATF5 included neural stem cells positive for CD133, a marker recently shown to be expressed by tumor-initiating cells in glioblastomas and other brain tumors (Singh et al, 2004). This contrasts with fully differentiated neurons, astrocytes and oligodendrocytes that do not show detectable expression of ATF5 in vivo (Angelastro et al, 2003Mason et al, 2005). Moreover, our studies revealed that ATF5 must be downregulated to permit neural progenitor cells to differentiate into neurons and glia.…”

“…Interfering with the function or expression of ATF5 promotes apoptosis of glioma cells, but not activated astrocytes, in vitro We have observed that interfering with the expression or function of ATF5 in neural progenitor cells causes them to exit the cell cycle and to undergo accelerated differentiation (Angelastro et al, 2003. We therefore next determined whether glioma cells respond similarly.…”

“…In rodent brains, proliferative neural progenitor cells express high levels of nuclear ATF5, whereas mature neurons and glia express little or no detectable levels of this protein (Angelastro et al, 2003Mason et al, 2005). We therefore assessed whether ATF5 might be expressed in highly proliferative glial tumors.…”

“…We have recently reported (Angelastro et al, 2003) that neural progenitor/stem cells in the developing brain express high levels of activating transcription factor 5 (ATF5; also referred to as ATFx), a member of the ATF/CREB family of bZip proteins (Jensen and Chiu, 1991;Nishizawa and Nagata, 1992;Pati et al, 1999;Hansen et al, 2002;Persengiev et al, 2002;Angelastro et al, 2003). Cells in the developing nervous system that expressed ATF5 included neural stem cells positive for CD133, a marker recently shown to be expressed by tumor-initiating cells in glioblastomas and other brain tumors (Singh et al, 2004).…”

“…Thus, constitutive expression of exogenous ATF5 maintains neural progenitor cells in a proliferative state both in vitro and in vivo, and represses their differentiation in the presence of extracellular signals such as NGF, NT3 and CNTF that otherwise promote differentiation and downregulation of endogenous ATF5. By contrast, loss of ATF5 function or expression achieved with a dominantnegative (d/n) form of ATF5 or with a small interfering RNA (siRNA), respectively, accelerates the differentiation of neural progenitors into nondividing neurons and glia (Angelastro et al, 2003Mason et al, 2005).…”