Mammalian scratch: A neural-specific snail family transcriptional repressor

Members of the Snail family of zinc finger transcription factors are known to play critical roles in neurogenesis in invertebrates, but none of these factors has been linked to vertebrate neuronal differentiation. We report t he isolation of a gene encoding a mammalian Snail family member that is res tricted to the nervous system. Human and murine Scratch (Scrt) share 81% an d 69% identity to Drosophila Scrt and the Caenorhabditis elegans neuronal a ntiapoptotic protein, CES-1, respectively, across the five zinc finger doma in. Expression of mammalian Scrt is predominantly confined to the brain and spinal cord, appearing in newly differentiating, postmitotic neurons and p ersisting into postnatal life. Additional expression is seen in the retina and, significantly, in neuroendocrine (NE) cells of the lung, In a parallel fashion, we detect hScrt expression in lung cancers with NE features, espe cially small cell lung cancer. hScrt shares the capacity of other Snail fam ily members to bind to E-box enhancer motifs, which are targets of basic he lix-loop-helix (bHLH) transcription factors. We show that hScrt directly an tagonizes the function of heterodimers of the proneural bHLH protein achaet e-scute homolog-1 and E12, leading to active transcriptional repression at E-box motifs. Thus, Scrt has the potential to function in newly differentia ting, postmitotic neurons and in cancers with NE features by modulating the action of bHLH transcription factors critical for neuronal differentiation .