NRSF (neuron-restrictive silencer factor, also designated XBR and REST for RE1-silencing factor) is a silencer protein that binds the DNA sequence element NRSE (neuron-restrictive silencer element). The binding of NRSF to the NRSE represses neuronal gene transcription in non-neuronal cells. Although NRSF is most highly expressed in non-neural tissues, it is also expressed in developing neurons and at low levels in the brain. NRSF contains nine zinc finger domains, but also exists as a C-terminally truncated form produced by alternative splicing. This variant, REST4, contains five of the zinc-finger domains and weakly binds DNA, yet is transported to the nucleus. NRSF associates with mSin3 and HDAC in ventricular myocytes, suggesting a role for NRSF outside the nervous system. Down-regulation of NRSF, which normally occurs upon neural differentiation, is necessary for the proper development of certain classes of neurons. NRSF is required to repress neuronal gene expression in vivo, in both extra-neural and undifferentiated neural tissue.