We recently used a differential display PCR screen to identify secreted and transmembrane proteins that are highly expressed in the developing rat basilar pons, a prominent ventral hindbrain nucleus used as a model for studies of neuronal migration, axon outgrowth, and axon-target recognition. Here we describe cloning and characterization of one of these molecules, now called MDGA1, and a closely related homologue, MDGA2. Analyses of the full-length coding region of MDGA1 and MDGA2 indicate that they encode proteins that comprise a novel subgroup of the Ig superfamily and have a unique structural organization consisting of six immunoglobulin (Ig)-like domains followed by a single MAM domain. Biochemical characterization demonstrates that MDGA1 and MDGA2 proteins are highly glycosylated, and that MDGA1 is tethered to the cell membrane by a GPI anchor. The MDGAs are differentially expressed by subpopulations of neurons in both the central and peripheral nervous systems, including neurons of the basilar pons, inferior olive, cerebellum, cerebral cortex, olfactory bulb, spinal cord, and dorsal root and trigeminal ganglia. Little or no MDGA expression is detected outside of the nervous system of developing rats. The similarity of MDGAs to other Ig-containing molecules and their temporal-spatial patterns of expression within restricted neuronal populations, for example migrating pontine neurons and D1 spinal interneurons, suggest a role for these novel proteins in regulating neuronal migration, as well as other aspects of neural development, including axon guidance.