2) was not due to reduced neurogenesis, and therefore explored the possibility that it reflected neuronal cell death. starting at E12.5, which was the earliest detectable phenotype, the latter reflected dramatic impairment of neuronal differentiation. Amazingly, the primary target cells of Dicer ablation, the neuroepithelial cells, and the neurogenic progenitors derived from them, were unaffected by UNC-2025 miRNA depletion with regard to cell cycle progression, cell division, differentiation and viability during the early stage of neurogenesis, and only underwent apoptosis starting at E14.5. Our results support the emerging concept that progenitors are less dependent on miRNAs than their differentiated progeny, and raise interesting perspectives as to the growth of somatic stem cells. Keywords:Dicer(Dicer 1) knockout, MicroRNAs, Neurogenesis == INTRODUCTION == The cerebral cortex, the site of higher brain function, has undergone dramatic growth during mammalian, and notably primate, development (Abdel-Mannan et al., 2008;Caviness et al., 1995;Molnar et al., 2006;Rakic, 1995;Rakic, 2007). The concomitant increase in neuron number is, in essence, due to an increase in neural progenitors that undergo neurogenic divisions (Gtz and Huttner, 2005;Kriegstein et al., 2006). You will find two principal classes of neural progenitors that generate the neurons of the mammalian cerebral cortex: (1) the progenitors dividing at the ventricular (apical) surface of the ventricular zone (VZ) (neuroepithelial cells, radial glia and short neural precursors, collectively referred to as apical progenitors); and (2) the progenitors that divide in the basal region of the VZ and in the subventricular zone (SVZ) (referred to as basal progenitors, also called intermediate, non-surface or SVZ progenitors) (Gtz and Huttner, 2005;Kriegstein et al., 2006). These unique neural progenitors can divide to generate either progenitors, neurons, or both. The molecular machinery that regulates the balance between apical and basal progenitors, and between their neurogenic and non-neurogenic divisions, is largely unknown. MicroRNAs (miRNAs) are a class of small RNAs that bind to specific mRNA targets, directing their degradation and/or repressing their translation (Hannon et al., 2006;Stefani and Slack, 2008). Approximately 70% of known miRNAs are expressed in ZNF346 the mammalian brain (Cao et al., 2006), and the level of many miRNAs changes dramatically during brain development (Krichevsky et UNC-2025 al., 2003;Miska et al., 2004;Sempere et al., 2004). Indeed, based UNC-2025 on observations obtained with cell culture models in vitro, miRNAs have been implicated in the control of neuronal differentiation (Conaco et al., 2006;Krichevsky et al., 2006;Makeyev et al., 2007;Smirnova et al., 2005;Wu and Belasco, 2005). Many of these investigations have focused on the in vitro role ofmiR-124, one of the most abundant miRNAs in the brain, which is highly enriched in neurons (De Pietri Tonelli et al., 2006;Hohjoh and Fukushima, 2007;Lagos-Quintana et al., 2002). These studies have revealed an important role of miRNAs in the differentiation of postmitotic neurons in vitro. To explore a possible role of miRNAs in neuronal differentiation during the development of the mammalian nervous system in vivo, recent studies have investigated the consequences of the genetic ablation of Dicer UNC-2025 (Dicer1 Mouse Genome Informatics), one of the essential enzymes for the production of endogenous small interfering RNAs (siRNAs) (Watanabe et al., 2008) and for miRNA maturation (Bernstein et al., 2001;Hutvagner et al., 2001). Dicer ablation in various specific subpopulations of neurons has been found to impair neuronal differentiation and cause neurodegeneration and neuronal cell death (Cuellar et al., 2008;Davis et al., 2008;Kim et al., 2007;Schaefer et al., 2007). Although the most recent of these reports [Cuellar et al., 2008;Davis et al., 2008(which appeared while the present study was being prepared UNC-2025 for.