cNSCL1 encodes a bHLH transcription factor and is specifically expressed in the developing nervous system. We used a replication-competent retrovirus to drive misexpression of cNSCL1 in chick embryos. We found that cNSCL1 misexpression was embryonic lethal and the embryos exhibited gross abnormalities. Many skeletal bones were abnormal and some were completely absent. Expression of BMP4 was reduced. The abnormalities were due to cNSCL1 misexpression in the systemic region, since microinjection of cNSCL1 retrovirus at one hindlimb primordium severely retarded its development, while other limbs on the same animal appeared normal. Similar misexpression of cNSCL2, a closely related bHLH gene, did not produce these phenotypes. Thus, the detrimental effects on embryonic development were specific to cNSCL1. These data indicate that cNSCL1 expression must be tightly regulated during development.