We describe a novel semaphorin family member, Sema VIa, with 25-36% sequence identity at the amino acid level in the semaphorin domain to previously published mouse homologues. This novel family member shares considerable homology with the best characterized murine semaphorin, Sema III (also known as SemD), at the 5' end but is divergent from Sema III near the 3' end because it contains a putative transmembrane domain. Remarkably, of the known semaphorins, Sema VIa bears the greatest structural similarity to insect Sema I, although it contains a much larger intracellular domain. We propose, therefore, that Sema VIa is the prototype of a new class (class VI) of semaphorins. In order to gain insights into potential functions of Sema VIa, we have compared mRNA expression of Sema VIa to that of Sema III during development. In the nervous system, Sema VIa is expressed in strikingly localized and transient patterns that are markedly different from those of Sema III. Interestingly, Sema VIa and Sema III frequently exhibit complementary or adjacent loci of expression. We suggest that Sema VIa may be important to nervous system development via a mechanism that involves cell-cell communication.