By screening a human fetal brain cDNA library under low stringency using cDNA encoding the mouse ligand of Cek5 as a probe, we have isolated a novel cDNA belonging to the EPLG gene family. This family encodes ligands of EPH-related tyrosine kinase receptors. Since the novel gene is the eighth member of the EPLG gene family, it is designated EPLG8. The deduced amino acid sequence of EPLG8 suggests that it encodes a transmembrane protein that is most related to those encoded by EPLG2 and EPLG5. We mapped the EPLG8 gene to human chromosome 17p11.2-p13.1 by PCR screening of human-rodent somatic cell hybrid panels. In the midterm fetus, EPLG8 mRNA is expressed at the highest level in brain, followed by heart, kidney, and lung. In the adult, EPLG8 mRNA expression is restricted to brain. These data suggest that LERK-8, the protein encoded by EPLG8, is important in brain development as well as in its maintenance. Moreover, since levels of EPLG8 expression were particularly high in several forebrain subregions compared to other brain subregions, LERK-8 may play a pivotal role in forebrain function.