ADAM2 promotes migration of neuroblasts in the rostral migratory stream to the olfactory bulb

Abstract

Neuroblasts migrate from the subventricular zone along the rostral migratory stream (RMS) to the olfactory bulb (OB). While the migration occurs by movement over other cells, the molecular mechanisms are poorly understood. We have found that ADAM2 (a disintegrin and metalloprotease 2) is expressed in migrating RMS neuroblasts and functions in their migration. The brains from ADAM2 knockout (KO) mice showed a smaller OB than that seen in wild-type (WT) mice at postnatal day 0. In addition, the RMS in ADAM2 KO mice appeared thinner and less voluminous in its rostral part and thicker in its caudal part. Estimates of migration in vivo using bromodeoxyuridine labeling revealed that neuroblasts from KO mice show a decreased migration rate compared with those from WT mice. Direct assays of migration by imaging living slices also showed a decreased migration speed and loss of directionality in the KO mice. This phenotype was similar to that seen in RMS containing slices from WT mice exposed to a peptide that mimicked the disintegrin loop of ADAM2. Finally, RMS explants from KO or WT mice that were cultured in Matrigel also revealed striking differences. The cells migrating out of explants from WT mice showed robust cell-cell interactions. In contrast, fewer cells migrated out of explants from ADAM2 KO mice, and those that did were largely dispersed and their migration inhibited. These experiments suggest that ADAM2 contributes to RMS migration, possibly through cell-cell interactions that mediate the rapid migration of the neuroblasts to their endpoint.