neuroepithelial cells , which constitute the wall of the neural tube , proliferate by repeating symmetric cell division , where each neuroepithelial cell divides into two neuroepithelial cells ( progenitor expansion phase , figure 1 ; alvarez - buylla et al . , 2001 ; fishell and kriegstein , 2003 ; fujita , 2003 ; gtz and huttner , 2005 ; miller and gauthier , 2007 ) . as the wall of the neural tube becomes thicker , neuroepithelial cells elongate and become radial glial cells , which have cell bodies in the ventricular zone , and radial fibers reaching the pial surface ( figure 1 ) . radial glial cells were previously thought of as specialized glial cells that guide neuronal migration . later , it was found that radial glial cells undergo asymmetric cell division , where each radial glial cell divides into two distinct cell types , a radial glial cell and an immature neuron or a basal progenitor ( neurogenic phase , figure 1 ; malatesta et al . , 2000 immature neurons migrate outside of the ventricular zone along radial fibers into the cortical plate , where these cells become mature neurons , whereas basal progenitors migrate into the subventricular zone ( svz ) , proliferate further and give rise to more neurons . radial glial cells give rise to many different types of neurons , initially deep layer neurons and then superficial layer neurons later , by repeating asymmetric cell division . radial glial cells also give rise to oligodendrocytes and ependymal cells and finally differentiate into astrocytes ( gliogenic phase , figure 1 ) . initially , neuroepithelial cells undergo repeated self - renewal by symmetric division ( progenitor expansion phase ) . as development proceeds , neuroepithelial cells elongate to become radial glial cells , which have cell bodies on the inner side ( called the ventricular zone ) of the neural tube and radial fibers that reach the outer surface after the production of neurons , some radial glial cells give rise to oligodendrocytes and ependymal cells . both neuroepithelial cells and radial glial cells are considered embryonic neural stem / progenitor cells . if neural stem / progenitor cells are prematurely depleted , not only is the total number of cells reduced but also later - born cell types are lacking , indicating that the maintenance of neural stem / progenitor cells until the final stage of development is essential to produce the proper number of cells and the full diversity of cell types ( hatakeyama et al . , 2004 ) . notch signaling has been shown to play an important role in the maintenance of neural stem / progenitor cells ( fortini , 2009 ; kopan and ilagan , 2009 ; pierfelice et al . , 2011 ) . here we review the recent progress on the mechanism and role of notch signaling in neural development . proneural genes such as the basic helix - loop - helix ( bhlh ) transcriptional activators mash1 and neurogenin2 ( ngn2 ) induce neuronal differentiation ( bertrand et al . , 2002 ; ross et al . , 2003 ) . these genes also induce the expression of notch ligands such as delta - like1 ( dll1 ) and jagged1 , which activate notch signaling in neighboring cells ( figure 2 ; castro et al . , 2006 ) . the ubiquitin ligase mindbomb is required in dll1-expressing cells for the dll1-induced activation of notch signaling ( ito et al . , 2003 ; yoon et al . , 2008 ) . upon activation of the transmembrane protein notch , the notch intracellular domain ( nicd ) is released from the transmembrane portion and transferred to the nucleus , where nicd forms a complex with the dna - binding protein rbpj and the transcriptional co - activator maml ( figure 2 ) . maml complex induces the expression of bhlh transcriptional repressors such as hes1 and hes5 ( honjo , 1996 ; artavanis - tsakonas et al . , 1999 ; ohtsuka et al . , 1999 ; hes1 and hes5 then repress the expression of proneural genes and dll1 , thereby leading to the inhibition of neuronal differentiation and the maintenance of neural stem / progenitor cells ( figure 2 ) . thus , neurons inhibit their neighboring cells from differentiating into the same cell types , a process known as lateral inhibition . this regulation maintains asymmetric division into a neural stem / progenitor cell and a differentiating daughter neuron . however , this regulation also suggests that the maintenance of neural stem / progenitor cells depends on neighboring neurons expressing dll1 , raising the question as to how neural stem / progenitor cells are maintained during the early stages before neurons are generated . proneural genes such as mash1 and ngn2 promote neuronal differentiation and induce the expression of dll1 , which in turn activates notch in neighboring cells . upon activation of notch , the notch intracellular domain ( nicd ) is released from the transmembrane portion and transferred to the nucleus , where it forms a complex with the dna - binding protein rbpj and the transcriptional co - activator maml . hes1 and hes5 then repress the expression of proneural genes and dll1 , thereby leading to the maintenance of neural stem / progenitor cells . proneural genes and dll1 are expressed in a salt - and - pepper pattern by neural stem / progenitor cells as early as e9.0 ( progenitor expansion phase ) in the developing mouse dorsal telencephalon ( our unpublished observation ) , where neuronal formation starts around e10.5e11.0 . in addition , hes1 is expressed at various levels by neural stem / progenitor cells ( shimojo et al . , 2008 ) . it is likely that proneural genes induce the expression of dll1 , which up - regulates hes1 expression in neighboring cells , suggesting that notch signaling is active in neural stem / progenitor cells before neurons are formed . this observation raises the question of why neurons are not formed during the progenitor expansion phase even though proneural genes are expressed . time - lapse imaging analysis revealed that hes1 expression oscillates in neural stem / progenitor cells ( masamizu et al . this negative feedback leads to the disappearance of hes1 mrna and protein because they are extremely unstable , but the disappearance of hes1 protein allows the next round of its expression . in this way , hes1 expression oscillates with a period of 23  h in neural stem / progenitor cells ( figure 3 ; hirata et al . , 2002 ) . protein expression exhibits an inverse correlation with ngn2 protein and dll1 mrna expression in neural stem / progenitor cells , suggesting that hes1 oscillation induces the oscillatory expression of ngn2 and dll1 by periodic repression ( shimojo et al . , 2008 ) . indeed , time - lapse imaging analysis revealed that ngn2 and dll1 expression oscillates in neural stem / progenitor cells , where hes1 expression oscillates , whereas their expression is sustained in differentiating neurons , where hes1 expression is repressed ( figure 4 ; shimojo et al . , 2008 ) . it is likely that ngn2 can not induce neuronal differentiation when its expression oscillates , probably because many downstream genes respond rather slowly to ngn2 expression . it seems that ngn2 induces neuronal differentiation only when its expression becomes sustained , and when its expression oscillates , only quickly responding genes such as dll1 are selectively induced . dll1 oscillations may lead to the mutual activation of notch signaling and the maintenance of neural stem / progenitor cells . thus , depending on its expression dynamics , ngn2 may lead to two opposite outcomes : when its expression oscillates , ngn2 induces the maintenance of neural stem / progenitor cells , but when its expression is sustained , ngn2 induces neuronal differentiation . hes1 expression oscillates with a period of 2  h in many cell types such as neural stem / progenitor cells and fibroblasts . this negative feedback leads to the disappearance of hes1 mrna and protein , because they are extremely unstable , allowing the next round of its expression . in this way hes1 expression oscillates with a period of 23  h in neural progenitor cells . in these cells , in contrast , the expression of ngn2 and dll1 is sustained in post - mitotic neurons , which lose hes1 expression . this reciprocal regulation is particularly important for the maintenance of neural stem / progenitor cells before the formation of neurons . the expression dynamics of ngn2 ( oscillatory versus sustained ) are regulated by hes1 ( oscillatory versus no expression ) . one possible mechanism is numb - mediated inhibition of notch signaling ( figure 2 ) . numb is asymmetrically distributed into a prospective neuron during asymmetric cell division ( shen et al . numb - expressing cells lose hes1 expression and differentiate into neurons , while numb - negative cells maintain hes1 expression ( ohtsuka et al . , 2006 ) . the above observations raise the possibility that ngn2 and dll1 oscillations enable the maintenance of neural stem / progenitor cells without the aid of neurons . when hes1 expression is low in a subset of cells ( cell 1 in the left panel of figure 5 ) , ngn2 and dll1 expression becomes high , leading to the activation of notch signaling and the up - regulation of hes1 in neighboring cells ( cell 2 in the left panel of figure 5 ) . in the latter cells , high levels of hes1 repress ngn2 and dll1 expression , but due to oscillations , hes1 expression becomes low after 1  h , while ngn2 and dll1 expression becomes high ( cell 2 in the right panel of figure 5 ) , leading to the activation of notch signaling in the former cells ( cell 1 in the right panel of figure 5 ) . in this way , dll1 oscillations lead to the mutual activation of notch signaling between neural stem / progenitor cells ( shimojo et al . , 2008 ) . these observations also suggest that notch signaling is not a one - way mechanism ( neuron to neural stem / progenitor ) , but functions by reciprocal transmission ( neural stem / progenitor to neural stem / progenitor ) . at later stages ( neurogenic phase ) , many differentiating neurons express dll1 in a sustained manner , thereby activating notch signaling in neural stem / progenitor cells . at these stages , ngn2 and dll1 expression mostly occurs in neurons but not in neural stem / progenitor cells , and therefore their expression is sustained , although hes1 expression in neural stem / progenitor cells oscillates even at these later stages . ngn2 and dll1 oscillations are regulated by hes1 oscillation in neural stem / progenitor cells . ngn2 oscillation may be advantageous for the maintenance / proliferation of neural stem / progenitor cells during the early stages of development , because it induces dll1 expression and activates notch signaling without promoting neuronal differentiation . a salt - and - pepper pattern induced by lateral inhibition is just a snapshot of oscillatory expression . it has been thought that lateral inhibition amplifies stochastic variation , creates a salt - and - pepper pattern in gene expression and selects subsets of cells for neuronal differentiation : ngn2-positive or dll1-positive neural stem / progenitor cells are initially selected to become neurons when the neurogenic phase starts , while negative cells remain neural stem / progenitor cells ( artavanis - tsakonas et al . , 1999 ) . however , time - lapse imaging analysis indicated that a salt - and - pepper pattern is just a snapshot of oscillatory expression ; therefore , neither ngn2-positive nor dll1-positive cells are initially selected to become neurons . thus , the traditional view of salt - and - pepper pattern formation induced by lateral inhibition should be revised ( kageyama et al . , 2008 ) . basal progenitors in the svz , which are derived from radial glial cells by tbr2 , retract their apical and basal processes and generally divide only once to generate two neurons ( sessa et al . , thus , basal progenitors have a limited proliferation ability . in these cells , hes1 and hes5 expression is down - regulated , suggesting that the notch - hes1/5 pathway is not active in basal progenitors ( mizutani et al . it was recently shown that the developing human neocortex has an expanded outer region in the svz ( osvz ) , and that progenitors in this region ( osvz progenitors ) divide multiple times and generate a large number of neurons ( fietz et al . , 2010 ; hansen et al . , 2010 osvz progenitors have radial glia - like morphology and extend radial fibers to the pial surface . however , they lack apical processes and therefore are not in contact with the ventricular surface . like radial glia , osvz progenitors express hes1 , and inhibition of notch signaling by treatment with a -secretase inhibitor induces osvz progenitors to differentiate into neurons or tbr2 basal progenitors ( hansen et al . , 2010 ) , suggesting that the notch - hes1 pathway is required for maintenance of osvz progenitors ( figure 6 ) . it is possible that the cells that migrate into the svz may become osvz progenitors when notch signaling is active , whereas they may become basal progenitors when notch signaling is inactive . it remains to be determined how notch signaling is regulated in the svz and whether hes1 expression oscillates in osvz progenitors , as observed in radial glia . osvz / ovz progenitors have radial glia - like morphology and extend radial fibers to the pial surface , but lack apical processes . these neurons seem to express notch ligands and activate notch signaling in their sibling osvz / ovz progenitors . similar cells called outer ventricular zone ( ovz ) progenitors are found in the developing mouse cortex ( shitamukai et al . , 2011 ) . ovz progenitors are located outside of the ventricular zone and retain radial fibers reaching the pial surface ( basal processes ) . these cells undergo asymmetric cell division , where each ovz progenitor divides into a daughter cell that inherits the radial fiber ( ovz progenitor ) and the other that does not . the one that inherits the radial fiber seems to repeat asymmetric cell division multiple times , while the other differentiates into post - mitotic neurons . the former cells ( ovz progenitors ) express hes1 , suggesting that notch signaling is activated in these cells ( figure 6 ) . interestingly , these daughter cells ( ovz progenitor and neuron ) maintain contact with each other for several hours , and neurons seem to express notch ligands and activate notch signaling in their sibling ovz progenitors ( figure 6 ; shitamukai et al . , 2011 ) . these observations suggest that asymmetric cell division is required to activate notch signaling in osvz or ovz progenitors by their sibling neurons . not all cells express hes1 in an oscillatory manner : cells in the roof plate , floor plate , and boundary regions , such as the isthmus , express hes1 in a sustained manner ( baek et al . , 2006 ) . furthermore , cells in these regions usually do not give rise to any neurons , probably because sustained hes1 expression constitutively represses the expression of proneural genes and cell cycle regulators . the introduction of sustained hes1 expression into neural stem / progenitor cells inhibits their proliferation and neuronal differentiation ( baek et al . , 2006 ) . in contrast , when he s genes are inactivated , the cells in the roof plate , floor plate , and boundary regions can differentiate into neurons ( baek et al . , 2006 ) . these results suggest that cells with sustained hes1 expression are rather dormant with regard to proliferation and differentiation . this feature is similar to the one observed in fibroblasts , where sustained hes1 over expression leads to reversible quiescence ( sang et al . , 2008 ) . the mechanism by which oscillatory versus sustained hes1 expression is regulated remains to be determined . in fibroblasts , jak2 activates stat3 by phosphorylation , and phosphorylated stat3 ( pstat3 ) induces socs3 expression , which in turn inhibits jak2 . due to this negative feedback , interestingly , blockade of this pathway with a jak inhibitor inhibits hes1 oscillations by stabilizing the hes1 protein , and hes1 expression becomes steady ( yoshiura et al . , 2007 ) . similarly , treatment with a jak inhibitor inhibits hes1 oscillations in neural stem / progenitor cells , suggesting that jak stat signaling is also involved in the regulation of hes1 oscillations in these cells ( shimojo et al . , 2008 ) . i d proteins , hlh factors without a basic region , form heterodimers with hes1 through their hlh domains and inhibit hes1 from binding to the n box in the hes1 promoter ( bai et al . , 2007 ) , suggesting that i d factors prevent hes1 from negative autoregulation . however , it remains to be determined whether i d factors lead to steady hes1 expression . oscillatory versus sustained hes1 expression leads to different outcomes in neural stem / progenitor cells . when its expression oscillates , neural stem / progenitor cells proliferate actively and differentiate into mature cells . by contrast , when its expression is sustained , neural stem / progenitor cells become dormant . similarly , oscillatory versus sustained ngn2 expression leads to different outcomes . when its expression is sustained , neural stem / progenitor cells differentiate into neurons . by contrast , when its expression oscillates , neural stem / progenitor cells remain undifferentiated . thus , not just the expression but also the dynamics of these genes are very important for the outcomes . the mechanism by which oscillatory versus sustained hes1 expression is regulated remains to be determined . in addition , the dynamics of downstream genes for hes1 and ngn2 oscillations are mostly unknown . the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest .