her4 encodes a zebrafish bHLH protein of the HAIRY-E(SPL) family. The gene is transcribed in a complex pattern in the developing nervous system and in the hypoblast. During early neurogenesis, her4 expression domains include the regions of the neural plate from which primary neurons arise, suggesting that the gene is involved in directing their development. Indeed, misexpression of specific her4 variants leads to a reduction in the number of primary neurons formed. The amino-terminal region of HER4, including the basic domain, and the region between the putative helix IV and the carboxy-terminal tetrapeptide WRPW are essential for this effect, since HER4 variants lacking either of these regions are non-functional. However, the carboxy-terminal WRPW itself is dispensable. We have examined the interrelationships between deltaD, deltaA, notch1, her4 and neurogenin1 by means of RNA injections. her4 is involved in a regulatory feedback loop which modulates the activity of the proneural gene neurogenin, and as a consequence, of deltaA and deltaD. Activation of notch1 leads to strong activation of her4, to suppression of neurogenin transcription and, ultimately, to a reduction in the number of primary neurons. These results suggest that her4 acts as a target of notch-mediated signals that regulate primary neurogenesis.