Robo3, a member of the Roundabout (ROBO) gene family, is an unconventional Robo receptor. It plays crucial roles in axon crossing of the CNS midline, especially in the development of commissural axons that connect both sides of the nervous system. It is associated with the SLIT/ROBO signaling pathway, which is important for the nervous system and embryonic development [1,3].

Many studies using transgenic mouse models have shown that Robo3 expression is mandatory for commissural axon guidance to the floor plate [1]. Mutations in human ROBO3 are responsible for horizontal gaze palsy with progressive scoliosis (HGPPS), an autosomal recessive disorder. Patients with HGPPS display midline crossing defects, including congenital absence or severe restriction of horizontal gaze and progressive scoliosis [2,3,4,6]. In non-M3 acute myeloid leukemia, high ROBO3 expression is associated with increased age at diagnosis, poorer risk classification, higher rates of TP53 and RUNX1 mutations, and significantly worse overall and event-free survival. It may also be a biomarker of inferior prognosis [5]. In pancreatic carcinoma, ROBO3 expression is up-regulated, and over-expression promotes cancer cell growth, invasion, and metastasis [7].

In conclusion, Robo3 is essential for the development of commissural circuits in the nervous system. The study of Robo3 through gene-knockout or conditional-knockout mouse models has revealed its role in HGPPS, non-M3 acute myeloid leukemia, and pancreatic carcinoma. Understanding Robo3's function provides insights into the development of the nervous system and the pathogenesis of related diseases, which may contribute to the development of new treatment strategies.