ADAMTS2 promotes radial migration by activating TGF-β signaling in the developing neocortex

The mammalian neocortex is formed by sequential radial migration of newborn excitatory neurons. Migrating neurons undergo a multipolar-to-bipolar transition at the subplate (SP) layer, where extracellular matrix (ECM) components are abundantly expressed. Here, we investigate the role of the ECM at the SP layer. We show that TGF-beta signaling-related ECM proteins, and their downstream effector, p-smad2/3, are selectively expressed in the SP layer. We also find that migrating neurons express a disintegrin and metalloproteinase with thrombospondin motif 2 (ADAMTS2), an ECM metalloproteinase, just below the SP layer. Knockdown and knockout of Adamts2 suppresses the multipolar-to-bipolar transition of migrating neurons and disturbs radial migration. Time-lapse luminescence imaging of TGF-beta signaling indicates that ADAMTS2 activates this signaling pathway in migrating neurons during the multipolar-to-bipolar transition at the SP layer. Overexpression of TGF-beta 2 in migrating neurons partially rescues migration defects in ADAMTS2 knockout mice. Our data suggest that ADAMTS2 secreted by the migrating multipolar neurons activates TGF-beta signaling by ECM remodeling of the SP layer, which might drive the multipolar to bipolar transition. ADAMTS2 is secreted by migratory neurons during the formation of the mammalian neocortex. ADAMTS2 promotes neuronal migration by activating TGF-beta signaling in migrating neurons during the multipolar-to-bipolar transition at the SP layer.ECM proteins are abundant in the subplate layer of the neocortex. Admts2 is upregulated during the migration of newborn neurons in the developing cortex. ADAMTS2 activates TGF-beta signaling perhaps by ECM remodeling of the SP layer, which might facilitate the multipolar to bipolar transition. ADAMTS2 is secreted by migratory neurons during the formation of the mammalian neocortex. ADAMTS2 promotes neuronal migration by activating TGF-beta signaling in migrating neurons during the multipolar-to-bipolar transition at the SP layer.