Pleiotrophin Signals Through ALK Receptor to Enhance the Growth of Neurons in the Presence of Inhibitory Chondroitin Sulfate Proteoglycans

Somnath J Gupta; Matthew A Churchward; Kathryn G Todd; Ian R Winship

doi:10.1177/26331055231186993

Pleiotrophin Signals Through ALK Receptor to Enhance the Growth of Neurons in the Presence of Inhibitory Chondroitin Sulfate Proteoglycans

Neurosci Insights. 2023 Jul 15:18:26331055231186993. doi: 10.1177/26331055231186993. eCollection 2023.

Authors

Somnath J Gupta^{1

2}, Matthew A Churchward^{1

3}, Kathryn G Todd^{1

2}, Ian R Winship^{1

2}

Affiliations

¹ Neurochemical Research Unit, Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
² Neuroscience and Mental Health Institute, University of Alberta, Edmonton, AB, Canada.
³ Department of Biology and Environmental Sciences, Concordia University of Edmonton, Edmonton, AB, Canada.

Abstract

Chondroitin sulfate proteoglycans (CSPGs), one of the major extracellular matrix components of the glial scar that surrounds central nervous system (CNS) injuries, are known to inhibit the regeneration of neurons. This study investigated whether pleiotrophin (PTN), a growth factor upregulated during early CNS development, can overcome the inhibition mediated by CSPGs and promote the neurite outgrowth of neurons in vitro. The data showed that a CSPG matrix inhibited the outgrowth of neurites in primary cortical neuron cultures compared to a control matrix. PTN elicited a dose-dependent increase in the neurite outgrowth even in the presence of the growth inhibitory CSPG matrix, with optimal growth at 15 ng mL^-1 of PTN (114.8% of neuronal outgrowth relative to laminin control). The growth-promoting effect of PTN was blocked by inhibition of the receptor anaplastic lymphoma kinase (ALK) by alectinib in a dose-dependent manner. Neurite outgrowth in the presence of this CSPG matrix was induced by activation of the protein kinase B (AKT) pathway, a key downstream mediator of ALK activation. This study identified PTN as a dose-dependent regulator of neurite outgrowth in primary cortical neurons cultured in the presence of a CSPG matrix and identified ALK activation as a key driver of PTN-induced growth.

Keywords: ALK; CSPGs; PTN; Plasticity; neuronal growth; neurons.