A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets

Abstract

Proneural genes such as Ascl1 are known to promote cell cycle exit and neuronal differentiation when expressed in neural progenitor cells. The mechanisms by which proneural genes activate neurogenesis-and, in particular, the genes that they regulate-however, are mostly unknown. We performed a genome-wide characterization of the transcriptional targets of Ascl1 in the embryonic brain and in neural stem cell cultures by location analysis and expression profiling of embryos overexpressing or mutant for Ascl1. The wide range of molecular and cellular functions represented among these targets suggests that Ascl1 directly controls the specification of neural progenitors as well as the later steps of neuronal differentiation and neurite outgrowth. Surprisingly, Ascl1 also regulates the expression of a large number of genes involved in cell cycle progression, including canonical cell cycle regulators and oncogenic transcription factors. Mutational analysis in the embryonic brain and manipulation of Ascl1 activity in neural stem cell cultures revealed that Ascl1 is indeed required for normal proliferation of neural progenitors. This study identified a novel and unexpected activity of the proneural gene Ascl1, and revealed a direct molecular link between the phase of expansion of neural progenitors and the subsequent phases of cell cycle exit and neuronal differentiation.

Cell cycle and lineage progression of neural progenitors in the ventricular-subventricular zones of adult mice

“…Ascl1, which activates expression of the proneurogenic program, also has pivotal roles in promoting the G 1 -to-S and G 2 -to-M transitions (23,51). During development Ascl1 and Hes1 oscillate in opposite directions during the cell cycle with high Hes1 expression in G 1 (52).…”

Sensitivity of Small Cell Lung Cancer to BET Inhibition Is Mediated by Regulation of ASCL1 Gene Expression

“…Our results have, therefore, provided further validation of ASCL1 as a driver of proliferation in SCLC. Although ASCL1 has been established as a proneural transcription factor that drives neuronal differentiation, it has also been found to drive the proliferation of neural progenitor cells by positive regulation of such genes as CDK2, E2F1, and BIRC5 (33). The proposed function of ASCL1 as an oncogenic transcription factor is, therefore, supported by its known function in upregulating growth promoting genes.…”

Expression Dynamics and Functions of Hes Factors in Development and Diseases

“…Mash1 promotes cell cycle exit and neuronal fate determination; Olig2 regulates oligodendrocyte specification, and Hes1 regulates the maintenance and proliferation of NS cells. Importantly, these three factors are also reported to function in other events: Mash1 upregulates the gene expression for cell cycle progression (Castro et al, 2011), Olig2 functions in NS cell proliferation (Ligon et al, 2007), and Hes1 promotes astrocyte differentiation (Ohtsuka et al, 2001). Thus, each of these factors has two contradictory functions: maintenance and proliferation of NS cells and determination of a specific cell fate.…”