Mad1 and c-Myc interactions during peripheral axonal regeneration

• Author / Creator

  Poitras, Trevor

• The peripheral nervous system (PNS) is often damaged by physical trauma or by diseases known as neuropathies. Currently, there are no effective treatments for augmenting repair of damaged nerves. Although the PNS is considered to be more plastic than the central nervous system, recovery outcomes in patients with neuropathy or physical damage are often poor. Molecular approaches have been investigated as a way to ramp up the regeneration response following damage. The list of proteins within peripheral neurons that restrict regrowth of axons is growing, with proteins such as PTEN, RB1, and RhoA as members of this list1–4.
  A thorough understanding of the mechanisms regulating axon regeneration will allow for the development of molecular approaches that can be applied within a clinical setting. Here we investigate the role of Mad1 and c-Myc in models of regeneration. c-Myc is a prominent transcription factor that is oncogenically activated in a wide variety of cancers. Under normal circumstances, it functions to cause the growth and proliferation of cells, but can be utilized by cancers cells to promote tumorigenesis. In order to execute c-Myc’s transcriptional functions, it must dimerize with Myc associated factor X (Max). This association can be inhibited by Mad1 to promote quiescence and differentiation of cells. We hypothesize that by inhibiting Mad1, there will be enhanced axonal regrowth through reduced competitive inhibition of Myc.
  We first identified that these important mediators are found within the PNS. In this thesis, through the use of small interfering RNA (siRNA), we investigated the role that Mad1 and c-Myc play within the regeneration response. We show that knockdown of Mad1 in dorsal root ganglion (DRG) cell cultures was sufficient to cause improvements in neurite extension. We also found that in vivo Mad1 knockdown within our sciatic crush injury model corresponded to improvements in functional recovery through behavioral and electrophysiological testing.
  Additionally, we found that knocking down c-Myc with siRNA in cultured DRG neurons had no effect on the ability of these neurons to grow projections. However, we did find a substantial growth reduction in our cultures treated with 10058-F4, a small molecule that inhibits N- and c-Myc’s association with Max.
  Taken together these findings suggest an important role for the Myc/Max/Mad1 network within the peripheral nervous system. The growth-promoting effects associated with Mad1 inhibition presents an intervention node that may potentially lead to novel therapeutic applications.

• Subjects / Keywords

  • c-Myc
  • Axon Regeneration
  • PNS
  • Peripheral nervous system
  • Mad1

• Graduation date

  Fall 2018

• Type of Item

  Thesis

• Degree

  Master of Science

• DOI

  https://doi.org/10.7939/R37941960

• License

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