TWE-PRIL reverse signaling suppresses sympathetic axon growth and tissue innervation

TWE-PRIL is a naturally-occurring fusion protein of components of two TNF superfamily members: the extracellular domain of APRIL and the intracellular and transmembrane domains of TWEAK with no known function. Here we show that April−/− mice (which lack APRIL and TWE-PRIL) exhibited overgrowth of sympathetic fibers in vivo, and sympathetic neurons cultured from these mice had significantly longer axons than neurons cultured from wild type littermates. Enhanced axon growth from sympathetic neurons cultured from April−/− mice was prevented by expressing full-length TWE-PRIL in these neurons but not by treating them with soluble APRIL. Soluble APRIL, however, enhanced axon growth from the sympathetic neurons of wild type mice. siRNA knockdown of TWE-PRIL but not siRNA knockdown of APRIL alone also enhanced axon growth from wild type sympathetic neurons. Our work reveals the first and physiologically relevant role for TWE-PRIL and suggests that it mediates reverse signaling.