REELIN SIGNALING COORDINATES DENDRITICINITIATION AND CELLULAR POSITIONING BY NEURITESTABILIZATION

Abstract

The laminar organization characteristic of the adult mammalian neocortex is a product of the precise coordination of neuronal proliferation, migration, and differentiation. Among these processes, the biological signals controlling apical dendrite initiation and targeting are not completely understood.The secreted ligand Reelin is a largeextracellular matrix glycoprotein localized to the axonal plexus of themarginal zone, and mutations areassociated with severe disruptions in cellular organization in laminated brain regions. Although the Reelin signaling pathway has been traditionally describedas a modulator of neuronal migration, recent evidence suggests Reelin controlsneuronal orientation and subsequent dendritogenesis into the overlying marginal zoneduring a period of early cortical development known as preplate splitting.To explicitly characterize how Reelin coordinates the transition between migration and dendritogenesis and controls polarized apical dendrite initiation and growth, an ex uteroexplant model of early cortical developmentwas used for fixed tissue and multiphoton live imaging analysis. Our investigations revealed the apical dendrite of cortical neurons emerges via direct transformation of the leading process during terminal translocation.Both throughoutand after this migratory phase, the dendriticarbor demonstrated significant increases in growth and branching, typically initiatedafter leading process entryinto the Reelin-rich marginal zone.In the absence of Reelin signaling, mutant cortices demonstrated a significant proportion of neurons that successfully translocated, but showed unstable arbors and marginal zone avoidance after migration arrest. Application of exogenous Reelin protein rescued dendritekinetics and polarity within4 hours, resultinginthe retraction of tangentially orienteddendritessimultaneous with the extension of a highly branched,apicallyoriented primary process. These findings suggesta precise role of Reelin signaling in early cortical development in proper neuronal polarization and stabledendrite outgrowth into the marginal zone, an area otherwiseexclusionary for dendrites. Furthermore, it is suggested that appropriate dendritic arbor elaborationinto the marginal zone may not only promote terminal translocation, but also definesthe final position of migration arrest.Thisbody of work thus offers an important advancement in understanding Reelin’s role in polarized dendritic outgrowth and the subsequent knock-on effectsassociated withperturbationsof this signaling pathway.