Ndr2 Kinase Controls Neurite Outgrowth and Dendritic Branching Through α₁ Integrin Expression

The serine/threonine kinase Ndr2 has been shown to control the inside-out activation of the β₁subunit of integrins and the formation of neurites in both primary neurons and neurally differentiated pheochromacytoma (PC12) cells. In this study, we demonstrate that Ndr2 kinase furthermore determines the substrate specificity of neurite extension in PC12 cells via expression of α₁β₁ integrins. We show that stable overexpression of Ndr2 in PC12 cells increases neurite growth and extension on poly-D-lysine substrate, likely involving an increased expression of active β₁ integrin in the growth tips of these cells. By contrast, the Ndr2 overexpressing cells do not show the α₁β₁ integrin-mediated enhancement of neurite growth on collagen IV substrate that can be seen in control cells. Moreover, they entirely fail to increase in response to activation of α₁β₁ integrins via a soluble KTS ligand and show a diminished accumulation of α₁ integrin in neurite tips, although the expression of this subunit is induced during differentiation to comparable levels as in control cells. Finally, we demonstrate that Ndr2 overexpression similarly inhibits the α₁β₁ integrin-dependent dendritic growth of primary hippocampal neurons on laminin 111 substrate. By contrast, lack of Ndr2 impairs the dendritic growth regardless of the substrate. Together, these results suggest that Ndr2 regulates α₁ integrin trafficking in addition to β₁ integrin subunit activation and thereby controls the neurite growth on different extracellular matrix (ECM) substrates.