Ventricular Netrin-1 deficiency leads to defective pyramidal decussation and mirror movement in mice

• Published in: Cell death & disease 2024-05, Vol.15 (5), p.343-8, Article 343
• Main Authors: Hu, Ling, Liu, Xi-Yue, Zhao, Li, Hu, Zhi-Bin, Li, Ze-Xuan, Liu, Wei-Tang, Song, Ning-Ning, Hu, Yun-Qing, Jiang, Luo-Peng, Zhang, Lei, Tao, Yun-Chao, Zhang, Qiong, Chen, Jia-Yin, Lang, Bing, Wang, Yu-Bing, Yue, Lei, Ding, Yu-Qiang
• Format: Article
• Language: English
• Subjects: 38; 38/1; 38/32; 631/136/1425; 631/378/1689; 82; 82/1; 82/29; 82/51; Animals; Antibodies; Axon guidance; Axonogenesis; Axons - metabolism; Axons - pathology; Biochemistry; Biomedical and Life Sciences; Brain; Cell Biology; Cell Culture; Congenital defects; Congenital diseases; Embryogenesis; Ethanol; Glial cells; Hybridization; Immunology; Kinases; Laboratory animals; Life Sciences; Medulla oblongata; Mice; Mice, Knockout; mRNA; Mutation; Nervous system; Netrin-1; Netrin-1 - genetics; Netrin-1 - metabolism; Neurobiology; Neurosciences; Pathogenesis; Protein transport; Proteins; Pyramidal tracts; Pyramidal Tracts - metabolism; Pyramidal Tracts - pathology; Radial glial cells; Signal transduction; Spinal cord; Substantia alba; Ventricle; Ventricular zone
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06719-1

The corticospinal tract (CST) is the principal neural pathway responsible for conducting voluntary movement in the vertebrate nervous system. Netrin-1 is a well-known guidance molecule for midline crossing of commissural axons during embryonic development. Families with inherited Netrin-1 mutations display congenital mirror movements (CMM), which are associated with malformations of pyramidal decussation in most cases. Here, we investigated the role of Netrin-1 in CST formation by generating conditional knockout (CKO) mice using a Gfap-driven Cre line. A large proportion of CST axons spread laterally in the ventral medulla oblongata, failed to decussate and descended in the ipsilateral spinal white matter of Ntn1 Gfap CKO mice. Netrin-1 mRNA was expressed in the ventral ventricular zone (VZ) and midline, while Netrin-1 protein was transported by radial glial cells to the ventral medulla, through which CST axons pass. The level of transported Netrin-1 protein was significantly reduced in Ntn1 Gfap CKO mice. In addition, Ntn1 Gfap CKO mice displayed increased symmetric movements. Our findings indicate that VZ-derived Netrin-1 deletion leads to an abnormal trajectory of the CST in the spinal cord due to the failure of CST midline crossing and provides novel evidence supporting the idea that the Netrin-1 signalling pathway is involved in the pathogenesis of CMM.