User:DuncanCleveland/sandbox
Slit/Robo Pathway
[edit]The roundabout receptor combines with a secreted factor, called slit to prevent the axon from growing back across the midline during axon guidance[1] . The slit protein is the primary ligand for the roundabout receptor, and binds through in the Ig1 and Ig2 domains. These domains bind to the D2 region in the slit[2]. The proteins are also believed to terminate the axon's attraction to netrin. The Slit/Robo complex also interacts with heparan sulfate proteoglycan proteins (HGSP). The absence of HGSP and heparan sulfates causes defects in axonal and retinal guidance in model organisms, indicating a relationship between the two pathways. The slit/robo pathway also plays a role in tangential neural migration.
Clinical Applications
[edit]Angiogenesis and Tumor Suppression
[edit]The Robo-4 receptor has been linked to angiogenesis in both mice and zebrafish. It is also present in human microvascular endothelial cells (HMVEC) and human umbilical vein endothelial cells (HUVEC). Exposure of Robo-4 to Slit-2 has inhibited angiogenesis. However, exposure to a protein that inhibits Slit-2 also inhibits angiogenesis[3] . Due to these inconclusive results, the role of Robo-4 in blood vessel growth is not completely understood.
Robo-1 has been linked to cancerous tumor growth and suppression. The Slit-2/Robo-1 pathway has been associated with tumor angiogenesis, leading to subsequent tumor growth. Slit-2 proteins have been identified in several varieties of tumors, including melanoma, breast cancer, small cell lung cancer, and bladder cancer. Furthermore, inhibition of the Slit-2/Robo-1 pathway via R5 and RoboN reduced tumor mass and volume, while also reducing microvessel density[4] . However, Slit-2 proteins have not been identified in all kinds of tumors, and other research suggests that Slit-2 expression may suppress tumors in small cell lung cancer and breast cancer[3] .
Dyslexia
[edit]The Robo-1 protein is thought to be one protein associated with dyslexia, possibly through chromosomal translocation.[5]
Robo-3/Rig-1 and HGPPS
[edit]A defect in the Robo-3/Rig-1 protein results in Horizontal gaze palsy with progressive scoliosis (HGPPS), a rare genetic disorder. HGPPS is characterized by a lack of horizontal eye movement within the socket (although vertical movement remains unaffected) and the gradual curvature of the spine throughout development[1] [6] . MRIs of HGPPS patients have also shown malformation of the brainstem, specifically the medulla[6] . The disorder is caused by a genetic mutation on chromosome 11, and is an autosomal recessive gene[7] . During normal brain development, Robo-3/Rig-1 decreases sensitivity of Robo1 to Slit proteins, allowing the axon to grow past the midline of the hindbrain[6] . This process allows neurons to cross to the other side of the brain, which is crucial for motor function as well as sensory processing. In patients with HGPPS, the absence of Robo-3/Rig-1 prevents the axon, specifically in the corticospinal tract and the trochlear nerve[1] , from growing past the midline. This abnormal growth of the hindbrain and spinal cord manifests itself as the symptoms associated with HGPPS.
References
[edit]- ^ a b c Purves, Dale (2012). Neuroscience. Sunderland, MN: Sinauer Associates, Inc. ISBN 978-2011038401.
- ^ Ypsilanti, Athena R.; Zagar, Yvrick; Chédotal, Alain (25 May 2010). "Moving away from the midline: new developments for Slit and Robo". Development. 137 (12): 1939–1952. doi:10.1242/dev.044511. PMID 20501589.
- ^ a b Klagsbrun, Michael; Eichmann, Anne (NaN undefined NaN). "A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis". Cytokine & Growth Factor Reviews. 16 (4–5): 535–548. doi:10.1016/j.cytogfr.2005.05.002. PMID 15979925.
{{cite journal}}: Check date values in:|date=(help) - ^ Wang, Biao; Xiao, Yang; Ding, Bei-Bei; Zhang, Na; Yuan, Xiao-bin; Gui, Lü; Qian, Kai-Xian; Duan, Shumin; Chen, Zhengjun; Rao, Yi; Geng, Jian-Guo (1 July 2003). "Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity". Cancer Cell. 4 (1): 19–29. doi:10.1016/S1535-6108(03)00164-8. PMID 12892710.
- ^ Galaburda, Albert M.; Loturco, Joseph; Ramus, Franck; Fitch, R Holly; Rosen, Glenn D. (1 October 2006). "From genes to behavior in developmental dyslexia". Nature Neuroscience. 9 (10): 1213–1217. doi:10.1038/nn1772. PMID 17001339.
- ^ a b c Butcher, James (NaN undefined NaN). "Mutations in ROBO3 cause HGPPS". The Lancet Neurology. 3 (6): 328. doi:10.1016/S1474-4422(04)00786-0. PMID 15176408.
{{cite journal}}: Check date values in:|date=(help) - ^ "Horizontal gaze palsy with progressive scoliosis". Retrieved 17 April 2012.