Robo3-KO Mouse

Robo3, a member of the Roundabout (ROBO) gene family, is a key receptor in the development of commissural systems in the nervous system. It is involved in axon guidance, particularly in the midline crossing of commissural axons, and is associated with the SLIT/ROBO signaling pathway [1,4]. This signaling pathway is crucial not only for nervous system development but also for embryonic development in general [5]. Genetic models, such as transgenic mouse models, have been instrumental in studying its function [1].

Many studies using transgenic mouse models have shown that Robo3 expression is essential 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 where patients display midline crossing defects [1,2,3,4,6]. Homozygous or compound heterozygous ROBO3 gene mutations cause HGPPS, characterized by congenital absence or severe restriction of horizontal gaze and progressive scoliosis [3]. To date, numerous ROBO3 mutations have been identified in HGPPS patients [3,4]. Additionally, high ROBO3 expression is associated with poor survival in non-M3 acute myeloid leukemia, and it may be a biomarker of inferior prognosis [5]. In pancreatic carcinoma, over-expression of ROBO3 promotes cancer cell growth, invasion, and metastasis [7].

In conclusion, Robo3 is vital for the development of commissural circuits in the nervous system. Model-based research, especially transgenic mouse models, has revealed its role in HGPPS, non-M3 acute myeloid leukemia, and pancreatic carcinoma. Understanding Robo3 function through these models provides insights into the underlying mechanisms of these diseases, potentially leading to new diagnostic and therapeutic strategies.

References:

1. Friocourt, François, Chédotal, Alain. 2017. The Robo3 receptor, a key player in the development, evolution, and function of commissural systems. In Developmental neurobiology, 77, 876-890. doi:10.1002/dneu.22478. https://pubmed.ncbi.nlm.nih.gov/28033646/

2. Pinero-Pinto, Elena, Pérez-Cabezas, Verónica, Tous-Rivera, Cristina, Benítez-Lugo, María-Luisa, Sánchez-González, María Carmen. 2020. Mutation in ROBO3 Gene in Patients with Horizontal Gaze Palsy with Progressive Scoliosis Syndrome: A Systematic Review. In International journal of environmental research and public health, 17, . doi:10.3390/ijerph17124467. https://pubmed.ncbi.nlm.nih.gov/32580277/

3. Yi, Sheng, Qin, Zailong, Zhou, Xunzhao, Chen, Biyan, Luo, Jingsi. 2023. Early onset horizontal gaze palsy and progressive scoliosis due to a noncanonical splicing-site variant and a missense variant in the ROBO3 gene. In Molecular genetics & genomic medicine, 11, e2215. doi:10.1002/mgg3.2215. https://pubmed.ncbi.nlm.nih.gov/37330975/

4. Harahsheh, Ehab Y, Moxley, Lauren E, Al-Amin, Matu, Deniz, Adnan, Osundiji, Mayowa. 2025. 20 years of ROBO3-related horizontal gaze palsy with progressive scoliosis: a mini-review. In Neurogenetics, 26, 30. doi:10.1007/s10048-025-00811-0. https://pubmed.ncbi.nlm.nih.gov/39960500/

5. Cai, Zhimei, Wei, Jifeng, Chen, Ze, Wang, Haiqing. 2021. High ROBO3 expression predicts poor survival in non-M3 acute myeloid leukemia. In Experimental biology and medicine (Maywood, N.J.), 246, 1184-1197. doi:10.1177/1535370220988246. https://pubmed.ncbi.nlm.nih.gov/33541130/

6. Sim, Bryan, Ng, Janice Wan Zhen, Sim, Donald Yuhui, Roca, Xavier, Jamuar, Saumya Shekhar. 2023. A novel intronic variant in ROBO3 associated with horizontal gaze palsy with progressive scoliosis: case report and literature review. In Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus, 27, 359-363. doi:10.1016/j.jaapos.2023.08.017. https://pubmed.ncbi.nlm.nih.gov/37931836/

7. Han, Shilong, Cao, Chuanwu, Tang, Tao, Zhang, Xiaoping, Li, Maoquan. 2015. ROBO3 promotes growth and metastasis of pancreatic carcinoma. In Cancer letters, 366, 61-70. doi:10.1016/j.canlet.2015.06.004. https://pubmed.ncbi.nlm.nih.gov/26070964/