Inhibition of DCLK1 promotes spinal cord injury recovery: implications for KATNA1 phosphorylation in microtubule-dependent neurite outgrowth

Functional recovery after spinal cord injury (SCI) remains challenging, requiring therapeutic targets. Here, we show that doublecortin-like kinase 1 (DCLK1) is upregulated after SCI in mice. Pharmacological inhibition of DCLK1 with DCLK1-IN-1 improved motor recovery, reduced glial scar formation and fibrosis, and preserved neurons at the lesion site. Mechanistically, we identified the microtubule-severing protein KATNA1 as a downstream target of DCLK1. DCLK1 directly phosphorylated KATNA1 at threonine 118 (T118), suppressing its microtubule-severing activity. DCLK1 overexpression inhibited, whereas DCLK1 knockdown or inhibition enhanced KATNA1 function. The T118D mutation reduced KATNA1 activity, while T118A resisted DCLK1-mediated suppression. In neurons, DCLK1 inhibited KATNA1-induced neurite outgrowth, whereas DCLK1 inhibition restored this effect. Together, these results identify DCLK1 as a promising therapeutic target for SCI and reveal a mechanism by which DCLK1 regulates KATNA1 phosphorylation to modulate microtubule severing and neurite outgrowth.