Abstract
Neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. However, the mechanism of neuritin in modulating neurite growth has not been elucidated. Here, using yeast two-hybrid we screened and discovered the interaction of neuritin and neuralized (NEURL1), which is an important regulator that can activate Notch signaling through promoting endocytosis of Notch ligand. And then we identified the interaction of neuritin and neuralized by co-immunoprecipitation (IP) assays, and clarified that neuritin and NEURL1 were co-localized on the cell membrane of SH-SY5Y cells. Moreover, neuritin significantly suppressed Notch ligand Jagged1 (JAG1) endocytosis promoted by NEURL1, and then inhibited the activation of Notch receptor Notch intracellular domain (NICD) and decreased the expression of downstream gene hairy and enhancer of split-1 (HES1). Importantly, the effect of neuritin on inhibiting Notch signaling was rescued by NEURL1, which indicated that neuritin is an upstream and negative regulator of NEURL1 to inhibit Notch signaling through interaction with NEURL1. Notably, recombinant neuritin restored the retraction of neurites caused by activation of Notch, and neurite growth stimulated by neuritin was partially blocked by NEURL1. These findings establish neuritin as an upstream and negative regulator of NEURL1 that inhibits Notch signaling to promote neurite growth. This mechanism connects neuritin with Notch signaling, and provides a valuable foundation for further investigation of neuritin’s role in neurodevelopment and neural plasticity.
Highlights
Neuritin was identified in a screen for activity-regulated genes involved in synaptic plasticity (Nedivi et al, 1993) and encodes an extracellular signaling molecule (Naeve et al, 1997)
Neuritinsuppressed endocytosis of JAG1 was mediated by NEURL1 (Figures 4A,B), since ectopic expression of NEURL1 was able to restore the inhibitory effects of neuritin on the Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1)
Our study revealed that neuritin is an upstream and negative regulator of NEURL1, and inhibits NEURL1-mediated Notch signaling to promote neurite growth
Summary
Neuritin ( known as CPG15) was identified in a screen for activity-regulated genes involved in synaptic plasticity (Nedivi et al, 1993) and encodes an extracellular signaling molecule (Naeve et al, 1997). Further studies revealed that neuritin supplies are abundant and activityindependent at early developmental stages when neuritin promotes dendritic and axonal growth and synaptic maturation (Nedivi et al, 1998; Cantallops et al, 2000; Javaherian and Cline, 2005). Neuritin protein is an important effector of nerve growth factor and androgen in enhancing peripheral nerve regeneration following injury (Fargo et al, 2008; Karamoysoyli et al, 2008). These results indicate that neuritin plays a key role in neural development and regeneration by promoting neurite outgrowth and synapse maturation. As a downstream effector of neurite outgrowth (Nedivi et al, 1998), the molecular mechanism explaining how neuritin promotes neurite growth remains obscure
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
