Reelin Counteracts Chondroitin Sulfate Proteoglycan-Mediated Cortical Dendrite Growth Inhibition

Abstract

Disruptions in neuronal dendrite development alter brain circuitry and are associated with debilitating neurological disorders. Nascent apical dendrites of cortical excitatory neurons project into the marginal zone (MZ), a cell-sparse layer characterized by intense chondroitin sulfate proteoglycan (CSPG) expression. Paradoxically, CSPGs are known to broadly inhibit neurite growth and regeneration. This raises the possibility that the growing apical dendrite is Significance Statement Appropriate dendritic development is essential for normal neuronal function throughout life. The area where most cortical dendrites initially project (the marginal zone) is 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. This study demonstrates that the growth of the apical dendrite is also inhibited by CSPGs. However, this inhibitory effect can be reversed by chondroitinase treatment and by activation of the Reelin signaling pathway. 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 functions beyond neuronal migration: from synaptogenesis to network activity modulation

“…As such, a disruption of PNNs reactivates visual plasticity 51,52 . Importantly, Reelin interacts and co-localizes with both CSPGs and HSPGs, as shown in two recent papers 13,53 . Along this line, an interesting recent study demonstrated a new role for Reelin in modulating cortical plasticity .…”

New insights into glial scar formation after spinal cord injury

“…CSPG-PTPRσ binding promotes monomerization of the receptor to increase its dephosphorylation activity, while HSPG-PTPRσ binding promotes clustering of the receptor and a decrease in dephosphorylating activity (Wu et al 2017). In the extracellular matrix milieu, the attention of the growth cone to the ratio of HSPGs to CSPGs as well as other extracellular proteins such as reelin (Zluhan et al 2020) or laminin (McKeon et al 1995) is, therefore, important in determining whether axon outgrowth proceeds. Following SCI, however, approaching axons are strongly inhibited by the preponderance of upregulated CSPGs found radiating from the glial scar (Davies et al 1997).…”

The CNS/PNS Extracellular Matrix Provides Instructive Guidance Cues to Neural Cells and Neuroregulatory Proteins in Neural Development and Repair

“…This also abrogates CS ligand binding to the inhibitory receptor RPTPσ. Thus, PTN increases dendrite regeneration in the adult cerebral cortex and axonal regeneration in the injured adult spinal cord [ 166 ]. PTN also increases neural proliferation and neurite outgrowth in cultured neurons.…”

“…Systemic delivery of a function-blocking peptide has been used to modulate RPTPσ interactions with CS-PGs to promote neuronal recovery following SCI. Inhibition of cortical dendritic growth by CS-PGs, can also be counteracted by reelin signalling [ 166 ]. Reelin is an extracellular signalling protein that regulates the alignment of radial neurons and rescues neurite outgrowth in the presence of CS-PGs.…”