Nrn1, also known as Neuritin-1, is a neurotrophic factor belonging to the neurotrophins family. It is crucial for neurodevelopment and synaptic plasticity, involved in neural cell survival, differentiation, axonal and dendritic growth, as well as synapse formation and maturation [2,3,4]. Nrn1 can activate the insulin receptor (IR) pathway to promote the transcription of CACNA1C [2]. It is also associated with multiple signaling pathways in different contexts, such as the Notch-STAT3 pathway in melanoma [1].

In melanoma, Nrn1 was found to interact directly with the cleaved intracellular domain of Notch1 and Notch3, reducing the expression of Hes1, which led to decreased sequestration of JAK and STAT3 in a phosphorylation complex. This ultimately increased the oncogenic signaling of STAT3, as indicated by the up-regulation of downstream targets like Vegf A, Mdr1, and cMet [1].

In schizophrenia, genetic epistasis between Nrn1 and BDNF or CACNA1C affected the disorder's clinical presentation, with certain interactions influencing symptom severity and functionality scores, as well as brain cortical structure [2]. Different haplotypes of Nrn1 were associated with early-onset schizophrenia, and the GTT haplotype was linked to worse working memory task performance and inefficient dorsolateral prefrontal cortex activity in early-onset patients [3].

In rats with optic nerve crush, Nrn1 overexpression attenuated retinal ganglion cell apoptosis, promoted axonal regeneration, and improved visual function by activating the Akt1 and Stat3 pathways and inhibiting the mitochondrial apoptotic pathway [4].

In conclusion, Nrn1 is essential for neurodevelopment, synaptic plasticity, and neural cell-related processes. Model-based research has revealed its significance in diseases such as melanoma, schizophrenia, and optic nerve injury. Understanding Nrn1's functions can potentially provide new insights into the pathogenesis of these diseases and offer novel therapeutic strategies.