Nrarp is a novel intracellular component of the Notch signaling pathway

The Lin12/Notch receptors regulate cell fate during embryogenesis by activa ting the expression of downstream target genes. These receptors signal via their intracellular domain (ICD), which is released from the plasma membran e by proteolytic processing and associates in the nucleus with the CSL fami ly of DNA-binding proteins to form a transcriptional activator. How the CSL /ICD complex activates transcription and how this complex is regulated duri ng development remains poorly understood. Here we describe Nrarp as a new i ntracellular component of the Notch signaling pathway in Xenopus embryos. N rarp is a member of the Delta-Notch synexpression group and encodes a small protein containing two ankyrin repeats. Nrarp expression is activated in X enopus embryos by the CSL-dependent Notch pathway. Conversely, overexpressi on of Nrarp in embryos blocks Notch signaling and inhibits the activation o f Notch target genes by ICD. We show that Nrarp forms a ternary complex wit h the ICD of XNotch1 and the CSL protein XSu(H) and that in embryos Nrarp p romotes the loss of ICD. By down-regulating ICD levels, Nrarp could functio n as a negative feedback regulator of Notch signaling that attenuates ICD-m ediated transcription.