THE MOUSE ROSTRAL CEREBELLAR MALFORMATION GENE ENCODES AN UNC-5-LIKE PROTEIN

Migration of neurons from proliferative zones to their functional site s is fundamental to the normal development of the central nervous syst em(1,2). Mice homozyous for the spontaneous rostral cerebellar malform ation mutation (rcm(s)) or a newly identified transgenic insertion all ele (rcm(tg)) exhibit cerebellar and midbrain defects, apparently as a result of abnormal neuronal migration. Laminar structure abnormalitie s in lateral regions of the rostral cerebellar cortex have been descri bed in homozygous rcm(5)-mice(3). We now demonstrate that the cerebell um of both rcm(5) and rcm(tg) homozygotes is smaller and has fewer fol ia than in the wild-type, ectopic cerebellar cells are present in midb rain regions by three days after birth, and there are abnormalities in postnatal cerebellar neuronal migration. We have cloned the rcm compl ementary DNA, which encodes a transmembrane receptor of the immunoglob ulin superfamily. The sequence of the rcm protein (Rcm) is highly simi lar to that of UNC-5, a Caenorhabditis elegans protein that is essenti al for dorsal guidance of pioneer axons and for the movement of cells away from the netrin ligand, which is encoded by the unc-6 gene(4-7). As Rcm is a member of a newly described family of vertebrate homologue s of UNC-5 which are netrin-binding proteins, our results indicate tha t UNC-5-like proteins may have a conserved function in mediating netri n-guided migrations(8).