Olson, Eric; Zluhan, Eric (2020)
      Appropriate dendritic development is essential for normal neuronal function throughout life. Disruptions in neuronal dendrite structure alter brain circuitry and are associated with debilitating neurological disorders.The Reelin signaling pathway is critical for proper cortical dendrite orientation and outgrowth. In Reelin null cortices (reeler), dendrites are unstable, retracting from and avoiding their normal target region called the marginal zone (MZ). This observation raises the possible existenceof a dendritic destabilizing cue in the MZ that can be counteracted by Reelin-signaling.The MZis cell sparse but highly enriched in chondroitin sulfate proteoglycans (CSPGs). While CSPGs are known to inhibit axonal outgrowth, their impact on dendritic growth is unclear.Here, we demonstrate that the growth of the apical dendrite is also inhibited by CSPGs. Soluble CSPGs and CSPG-patterned stripes are inhibitory to dendrite growth, butthis inhibitory effect can be reversed by CSPG ablation via chondroitinase treatment and by activation of the Reelin signaling pathway. In reeler explants, chondroitinase treatment rescues dendrite growth into MZ. Prior studies have shown that the serine threonine kinase Akt is essential for Reelin-dependent dendritic growthand also functions in CSPG-dependent neurite retraction. We find that CSPGs induce Akt dephosphorylation which isreversed by Reelin addition. CSPG presence had no effect on the cytoplasmic adaptor Dab1, which is rapidly phosphorylated in response to Reelin. Dab1-deficient neurons were sensitive to CSPG stimulation, but Reelin-dependent phosphorylation was blunted. This suggests that the extracellular signals imparted on dendrites by Reelin and CSPGs at the MZ converge intracellularly downstream of Dab1 atthe level of Akt to regulate dendritogenesis in the MZ.Disruptions in Reelin signaling cause intellectual disability and have been linked to autism. Thus, these findings identify a context in which Reelin signaling operates and provide insight into the underlying mechanism of neurodevelopmental disorders.
    • Reelin Signaling in Oligodendrocyte Progenitor Cell Migration

      Osterhout, Donna; BHATTI, HARNEET (2016)
      Oligodendroglial progenitor cells (OPCs) are the precursors to the myelinating oligodendrocytes in the central nervous system (CNS). These cells are produced in the ventral neuroepithelium at later stages of cortical development, migrating into the cortex where they contact axons and differentiate, ultimately forming a myelin membrane. During the process of differentiation, OPCs undergo significant morphological changes, extending many processes which will make contact with axons. Once in contact with an axon, the oligodendrocyte process expands and begins to form the myelin membrane which will ensheathe the axon. Reelin is a highly conserved secretory glycoprotein, which has acritical role in directing neuronal migration. Reelin orchestrates the proper cortical layer formation and neuronal organization during brain development. In the absence of Reelin, the cerebral crotex is disorganized, with inverted cortical layers, generating devastating biological effects. Reelin acts through several cellular receptors, activating numerous downstream effectors and complex signaling cascades. If elements of the Reelin signalling pathway are disrupted,similar defects in migration can occur.Oligodendroglial cells, from the early progenitor cells to the mature myelinating cells secrete Reelin, but also express a receptor for Reelin and criticalelements of the intracellular Reelin signaling pathways. It is not known if these cells canrespond to Reelin. In this thesis, we examined the effects of Reelin on oligodendroglial cells, using both in vitroand in vivomethods. We demostrate a potentialrole for Reelin in modulating oligodendrocyte migration, but also identify a novel aspect ofReelin signalling in the biology of oligodendroglia.