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Discovery of New Roles for Chondroitin Sulfate in Neurotrophin Signaling and Retinotopic Development


Rogers, Claude Joseph (2013) Discovery of New Roles for Chondroitin Sulfate in Neurotrophin Signaling and Retinotopic Development. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9N58JCD.


Chondroitin sulfate (CS), a member of the glycosaminoglycan family of linear polysaccharides, is involved in the formation and maintenance of neuronal networks. CS has dual roles in regulating neuronal morphology: promoting or inhibiting neuronal outgrowth, depending on the context. A single sulfated epitope, CS-E, is capable of inducing both types of activity.

Members of the neurotrophin (NT) family of growth factors are required for CS- E-induced neurite outgrowth in hippocampal neurons. Here, we demonstrate that CS is capable of forming ternary complexes with NTs and their receptors. These complexes were discovered using a novel, carbohydrate microarray-based approach that allows for the rapid screening of such interactions. To support these findings, we computationally determined the CS-E-binding site of the complexes, suggesting a structural basis for the interaction. In addition, we showed that CS-E is capable of attenuating NT signaling in cells, consistent with our computational and microarray data. This is the first demonstration that CS-E is involved in NT signaling and that CS is capable of supporting multimeric signaling complexes.

In addition to stimulating growth factor signaling, CS has been known to repulsively guide retinal ganglion cell (RGC) axons for over twenty years. However, its function in vivo is unknown. RGCs are the only neuron type that transmits visual information to the brain, and their guidance, which maps a topographic projection of the retina to the superior colliculus (SC), is tightly regulated. Here, we show that CS-E is required for the proper formation of this topographic order. CS-E, but not the other major sulfation patterns, is a repellent guidance cue for RGC axons, with a graded activity profile from low to high along the dorsal-ventral axis of the retina, congruent with EphB3 expression. EphB3 binds specifically to CS-E with physiologically relevant affinity, and is required for CS-E-mediated guidance. CS-E-null mice have defects in topographic mapping in which ventral axons form ectopic termina- tions medial to their correct location in the SC. These results indicate that CS is a repulsive guidance cue required to map the dorsal-ventral axis of the retina along the lateral-medial axis of the SC. This is the first report of a non-protein topographical guidance cue.

Item Type:Thesis (Dissertation (Ph.D.))
Subject Keywords:Glycosaminoglycan; Chondroitin Sulfate; Retinotopic Mapping; Development; Neurotrophin
Degree Grantor:California Institute of Technology
Division:Chemistry and Chemical Engineering
Major Option:Chemistry
Thesis Availability:Public (worldwide access)
Research Advisor(s):
  • Hsieh-Wilson, Linda C.
Thesis Committee:
  • Dougherty, Dennis A. (chair)
  • Shan, Shu-ou
  • Rees, Douglas C.
  • Zinn, Kai George
  • Hsieh-Wilson, Linda C.
Defense Date:11 October 2012
Funding AgencyGrant Number
NIH Training Grant5T32 GM07616
NIH Training GrantR01 GM093627
Caltech Special Institute FellowshipUNSPECIFIED
Record Number:CaltechTHESIS:01272013-150337805
Persistent URL:
Related URLs:
URLURL TypeDescription DOIArticle adapted for ch. 3 adapted for Appendix A
Default Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:7444
Deposited By: Claude Rogers
Deposited On:06 Mar 2017 22:26
Last Modified:03 Oct 2019 23:58

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