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.

Mechanisms of Neurogenesis in the Normal and Injured Adult Brain

“…31,32 Extracellular matrix-related molecules such as α6β1-integrin and ADAM2 protease are also involved in neuroblast chain formation. [33][34][35] These findings raise the possibility that various extracellular stimuli actively regulate the chain formation of neuroblasts.…”

Expression of seven members of the ADAM family in developing chicken spinal cord

“…For example, knockdown of ADAM19 in Xenopus decreases the numbers of neurons and neural crest cells (Neuner et al, 2009). ADAM2 contributes the neuroblasts migrating to the olfactory bulb (Murase et al, 2008). Proteolytic processing of the neural cell adhesion molecule (NCAM) by ADAM17 is involved in NCAM-mediated neurite outgrowth (Kalus et al, 2006).…”

Neural Stem Cells: Exogenous and Endogenous Promising Therapies for Stroke

“…The possible mechanism of regulation might be the high capacity of ADAMs to bind to integrins, which, as previously mentioned, are fundamental to this process (Yang et al, 2006). ADAMs are widely expressed in the CNS and approximately 17 different ADAMs have been detected in the CNS, however, so far, only ADAM2 and ADAM21 are directly related to SVZ-RMS cell dynamics (Murase et al, 2008;Yang et al, 2005).…”

“…Lack of ADAM2 results in defects in migration and morphological alterations of the RMS, which is caudally thicker and rostrally thinner, as seen in ADAM2-null mice. ADAM2 probably regulates migration by promoting polarized cell morphology that enables migration, since ADAM2-knockout mice present short leading cell processes and a slow cell migration rate compared with neuroblasts in wild type mice (Murase et al, 2008).…”