No Rest for REST: REST/NRSF Regulation of NeurogenesisSelected ReadingPreviews499easily studied, since dPatj mutant flies are viable andshow no detectable apical-basal polarity defects (Pie-lage et al., 2003). Loss of dPatj activity does not ran-domize the R3/R4 decision, but, interestingly, symmet-rical R3/R3 ommatidia are seen in dPatj mutant flies.R3/R3 ommatidia are associated with high Fz activity.Furthermore, a 2-fold reduction of dPatj activity en-hances the gain-of-function phenotypes induced by Fzoverexpression. Thus, dPatj appears to antagonize FzPCP signaling. Whether this effect of dPatj on Fz activ-ity is mediated via its direct interaction with Fz, how-ever, is not entirely clear since a Fz-GFP C-terminal fu-sion protein lacking the C-terminal PBM involved indPatj binding localizes apically and rescues a completeloss of fz activity (Strutt, 2001).What could be the functional significance of theaPKC- and dPatj-mediated inhibition of apical Fz? It isimportant to note that Fz localizes at the apical cortexof eye epithelial cells long before they differentiate (i.e.,anterior to the eye morphogenetic furrow) and acquiretheir second polarity axis. Although it is not entirelyclear when Fz signals to establish PCP (Strutt andStrutt, 2002), Fz appears to signal to establish PCP onlyduring a brief period of time preceding the R3/R4 deci-sion. Thus, one hypothesis is that aPKC-mediatedphosphorylation of Fz defines this temporal window ofFz signaling by inhibiting Fz prior to and after thisperiod. Consistent with this hypothesis, the level ofdPatj accumulation is specifically downregulated in theR3/R4 precursor cells when PCP signaling is thoughtto occur. Moreover, this downregulation of dPatj doesnot depend on Fz signaling, as it is still observed inPCP mutant flies. Additionally, the level of Bazooka(Baz; the Drosophila Par3 homologue) is upregulated inthe R3/R4 precursor cells, and this upregulation alsodoes not depend on PCP signaling. Loss of baz activityin clones results in symmetrical R4/R4 ommatidia (as-sociated with low Fz signaling), and a 2-fold reductionof baz activity suppresses Fz overexpression pheno-types. These data, therefore, suggest that Baz posi-tively regulates Fz signaling. Baz does not appear toact by regulating the levels of dPatj. Whether Baz actsby antagonizing aPKC activity or by yet another mecha-nism remains to be determined. Together, these obser-vations suggest a model whereby the downregulationof dPatj and upregulation of Baz release Fz from aPKC-mediated inhibition and thus define when Fz signalingis active and PCP is established (Figure 1). One predic-tion of this model is that PCP, as reflected by the asym-metric distribution of Fz at the apical cortex of R3/R4cell pairs, may be established earlier in developingdPatj mutant eyes.The notions that PCP signaling is inhibited by com-ponents of apical polarity complexes and that this inhi-bition is important to define when PCP is establishedare novel. Moreover, inhibition of Fz PCP signaling byapical-basal polarity complexes may reflect a moregeneral property of cell polarity regulation, which is thatcells may more easily interpret a single polarity cue atone time. Accordingly, one first response of polarizedcells to a novel polarity information such as PCP maybe to downregulate preexisting polarity cues. Futurestudies will no doubt test whether PCP formation in theeye actually requires a transient downregulation of api-cal-basal polarity in R3/R4 cells.François SchweisguthEcole Normale SupérieureCNRS UMR854246 rue d’Ulm75230 Paris Cedex 05FranceSelected ReadingDjiane, A., Yogev, S., and Mlodzik, M. (2005). Cell 121, this issue,621–631.Eaton, S. (1997). Curr. Opin. Cell Biol. 9, 860–866.Hurd, T.W., Gao, L., Roh, M.H., Macara, I.G., and Margolis, B.(2003). Nat. Cell Biol. 5, 137–142.Knust, E., and Bossinger, O. (2002). Science 298, 1955–1959.Pielage, J., Stork, T., Bunse, I., and Klambt, C. (2003). Dev. Cell 5,841–851.Strutt, D. (2001). Mol. Cell 7, 367–375.Strutt, D. (2003). Development 130, 4501–4513.Strutt, H., and Strutt, D. (2002). Dev. Cell 3, 851–863.Wang, Q., Hurd, T.W., and Margolis, B. (2004). J. Biol. Chem. 279,30715–30721.Wu, J., Klein, T.J., and Mlodzik, M. (2004). PLoS Biol. 2, e158.10.1371/journal.pbio.0020158DOI 10.1016/j.cell.2005.05.006No Rest for REST:REST/NRSF Regulationof NeurogenesisEpigenetic strategies control the orderly acquisitionand maintenance of neuronal traits. A complex net-work of transcriptional repressors and corepressorsmediates gene specificity for these strategies. In thisissue of Cell, a study by Ballas and coworkers (Ballaset al., 2005) provides insight into the early lineagecommitment events during neurogenesis. This studydemonstrates that regulation of the REST/NRSF tran-scriptional repressor plays a fundamental role in theprogression of pluripotent cells to lineage-restrictedneural progenitors.The molecular basis for diversity in the function of thevarious cell types in multicellular organisms is cell-type-specific gene expression. Neurons differ from anyother cells in the organism by containing a specific setof proteins that are critical for execution of the special-ized functions in the nervous system and are encodedby genes that must be expressed in a neuron-specificmanner. Neuronal differentiation and active regulationof the differentiated state are controlled by the balancebetween negative and positive regulators, which are criti-cal for ensuring continuous control of neuron-specificgene transcription in every neuron throughout adulthood.Cell500Figure 1. Multiple Strategies for Derepres-sion of REST/NRSF-Regulated NeuronalGenesThe regulatory mechanisms that restrict the expressionof these genes exclusively to the central nervous sys-tem are therefore fundamental for the development andfunction of the brain.In 1995, two groups independently identified a geneencoding a zinc finger protein that was suggested tofunction as a master regulator of the neuronal pheno-type. The transcription factor REST, an RE1-silencingtranscription factor (Chong et al., 1995), also known asneuron-restrictive silencer factor NRSF (Schoenherrand Anderson, 1995) blocks transcription of its targetgenes by binding to a specific consensus 21 bp RE1binding site/neuron-restrictive silencer element (RE1/NRSE) that is present in the target genes’ regulatoryregions. REST/NRSF functions very effectively as atranscriptional repressor at a distance and is able