Headshot of Travis Lee Dickendesher

Research

Novel Mechanisms of Axonal Growth Inhibition Following Central Nervous System Injury

My dissertation work is largely focused on the environmental barriers in the adult mammalian central nervous system (CNS) that prevent axon regeneration following injury or disease: myelin-associated inhibitors (MAIs) and chondroitin sulfate proteoglycans (CSPGs). Several MAIs have been identified and characterized at the molecular level, including myelin-associated glycoprotein (MAG), the reticulon family member Nogo-A, and oligodendrocyte myelin glycoprotein (OMgp). In addition, a glial scar forms at the injury site, composed of reactive astrocytes, which express high levels of inhibitory CSPGs that block regenerative axonal growth.

In order to exert growth inhibition, MAIs and CSPGs must bind to axonal surface receptors and initiate downstream signaling cascades. Identifying and characterizing MAI and CSPG receptors has become an important focus in the field of nervous system regeneration, as these molecules represent potential targets for therapeutic intervention.

The Nogo receptors (NgR1, NgR2, and NgR3) form a small subfamily of proteins, of which NgR1 and NgR2 have been shown to act as receptors for MAIs. We have recently identified a novel interaction between select members of the Nogo receptor family and CSPGs. NgR1 and NgR3 bind with high affinity and selectivity to the sugar moiety of CSPGs. In vitro, primary neurons isolated from mice lacking both NgR1 and NgR3 (NgR13 null) grow longer neurites on substrate-adsorbed CSPGs than neurons isolated from wildtype, NgR1 null, NgR2 null, NgR3 null, or NgR12 null mice, suggesting that NgR1 and NgR3 are functionally redundant CSPG receptors. Nogo receptor triple mutant mice (NgR123 null), but not single mutants, show enhanced axonal regeneration in vivo following optic nerve crush injury. The combined loss of NgR1 and NgR3 (NgR13 null), but not NgR1 and NgR2 (NgR12 null), is sufficient to mimic the NgR123 null regeneration phenotype. To examine whether these regenerating fibers are functional, we are currently performing compound action potential recordings on acutely isolated optic nerves. These results thus identify NgR1 and NgR3 as novel CSPG receptors, demonstrate functional redundancy among CSPG receptors, and provide unexpected evidence for shared mechanisms of MAI and CSPG inhibition.

A second focus of my dissertation work is a detailed characterization of the structural and functional relationship between MAG and its high-affinity receptors NgR1, NgR2, and paired immunoglobulin-like receptor B (PirB). In addition to its role in axonal growth inhibition, MAG has recently been shown to promote resistance to axonal degeneration following various insults (excitotoxicity, Vincristine treatment, etc). I am currently using a combination of biochemistry, cell culture, and mouse genetics to assess the role of these MAG receptors in both growth inhibition and axonal protection. In a collaboration with the Gonias laboratory at UCSD, I am also characterizing a newly identified receptor for MAG: the low density lipoprotein receptor-related protein-1 (LRP1). We are currently performing mechanistic studies to assess the role of LRP1, individually and in combination with other known MAG receptors, in MAG-mediated growth inhibition and axonal protection in vitro and in vivo following insult or injury.


Publications

Representative Publications

  • Stiles TL*, Dickendesher TL*, Gaultier A, Fernandez-Castaneda A, Mantuano E, Giger RJ, Gonias SL. LDL receptor-related protein-1 is a sialic acid-independent receptor for myelin-associated glycoprotein (MAG) that functions in neurite outgrowth inhibition by MAG and CNS myelin (in press, J Cell Sci).
    • * denotes equal contribution
  • Dickendesher TL, Duan Y, Giger RJ. Axon regeneration (book chapter). P. Rakic & J. Rubenstein (Eds.) Comprehensive Developmental Neuroscience (in press, Elsevier).
  • Dickendesher TL, Baldwin KT, Mironova YA, Koriyama Y, Raiker SJ, Askew KL, Wood A, Geoffroy CG, Zheng B, Liepmann CD, Katagiri Y, Benowitz LI, Geller HM, Giger RJ (2012) NgR1 and NgR3 are receptors for chondroitin sulfate proteoglycans. Nat Neurosci 15(5):703-12.
  • Dickendesher TL, Giger RJ (2011) VEGF shows its attractive side at the midline. Neuron 70(5):808-12.
  • King IL, Dickendesher TL, and Segal BM (2009) Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood. Apr 2;113(14):3190-7.
  • Brackenbury WJ, Davis TH, Chen C, Slat EA, Detrow MJ, Dickendesher TL, Ranscht B, and Isom LL (2008) Voltage-gated Na+ channel β1 subunit-mediated neurite outgrowth requires fyn kinase and contributes to postnatal CNS development in vivo. J Neurosci. Mar 19;28(12):3246-56.
  • Chen C, Dickendesher TL, Oyama F, Miyazaki H, Nukina N, and Isom LL (2007). Floxed allele for conditional inactivation of the voltage-gated sodium channel β1 subunit Scn1b. Genesis. Sep;45(9):547-53.