NRSF/REST is required in vivo for repression of multiple neuronal target genes during embryogenesis

Abstract

The neuron-restrictive silencer factor NRSF (also known as REST and XBR) can silence transcription from neuronal promoters in non-neuronal cell lines, but its function during normal development is unknown. In mice, a targeted mutation of Rest, the gene encoding NRSF, caused derepression of neuron-specific tubulin in a subset of non-neural tissues and embryonic lethality. Mosaic inhibition of NRSF in chicken embryos, using a dominant-negative form of NRSF, also caused derepression of neuronal tubulin, as well as of several other neuronal target genes, in both non-neural tissues and central nervous system neuronal progenitors. These results indicate that NRSF is required to repress neuronal gene expression in vivo, in both extra-neural and undifferentiated neural tissue.

A transgenic mouse Class‐III β tubulin reporter using yellow fluorescent protein

“…It is interesting to note that in this work, the β-tubulin III -YFP construct introduced into the mouse did not include the NRSE, The neuronal accumulation, as well as the lack of non-neuronal accumulation of YFP, provides strong evidence that the control of β-tubulin III expression is not solely dependent on NRSF (Dennis et al, 2002). One possible mechanism by which this may occur has been presented previously (Chen et al, 1998). A further comparison of the rat (Dennis et al, 2002) and mouse β-tubulin III promoters shows that both upstream regions possess similar classes of transcription factor binding sites including AP2, C/EB, E-box, and SP1 sites, although the precise locations upstream from the TATA box are often not identical (Dennis et al, 2002;Uittenbogaard and Chiaramello, 2002).…”

“…The mouse β-tubulin III NRSE is located in the first intron (Schoenherr et al, 1996). Anderson and colleagues (Chen et al, 1998;Schoenherr and Anderson, 1995;Schoenherr et al, 1996) have shown that the β-tubulin III gene is regulated in part by the NRSF. It is interesting to note that in this work, the β-tubulin III -YFP construct introduced into the mouse did not include the NRSE, The neuronal accumulation, as well as the lack of non-neuronal accumulation of YFP, provides strong evidence that the control of β-tubulin III expression is not solely dependent on NRSF (Dennis et al, 2002).…”

Epigenetics in development

“…Repressor element 1 (RE-1) silencing transcription factor/neuron restrictive silencing factor (REST/NRSF) is a zinc finger protein that triggers epigenetic silencing of neuronal genes . In mice lacking REST/ NRSF, the neural-specific gene ␤III-tubulin is expressed in some non-neural tissues, but many cell types are unaffected (Chen et al, 1998). However the mice die at E11.5, precluding insight into the roles for REST in nervous system development.…”

“…This is especially evident in studies of stem cells where much of the cells chromatin appears to carry a "bivalent" or mixed signature comprising both "active" and repressed' marks (Azuara et al, 2006;Bernstein et al, 2006). Also, remember that in the RESTϪ/Ϫ embryo, very few target genes were precociously activated (Chen et al, 1998). This of course could be due to absence of appropriate activators.…”

Histone Regulation in the CNS: Basic Principles of Epigenetic Plasticity

“…For example, BAF family complex members Brg1, BAF57, and BAF170 have been shown to associate as a larger complex with the neural restrictive silencing factor (NRSF/REST) and its co-repressors (eg, Sin3A, CoREST, and MeCP2) in non-neuronal cells (Ooi et al, 2006). NRSF/REST expression is restricted to nonneuronal cells, and as a zinc finger domain containing transcription factor, binds to target motifs (RE1) and represses transcription of neuronal specific genes through association with its co-repressors (Chong et al, 1995;Chen et al, 1998;Lunyak et al, 2002;Ballas et al, 2005). Recent evidence demonstrates that the repressive activity of NRSF/ REST requires a functional bromodomain interaction with Brg1, whereby Brg1 is recruited to RE1 sites to synergistically control the expression of neuronal gene programs in non-neuronal cells (Ooi et al, 2006).…”