The role of novel genes in CNS axon regeneration

Almutiri, Sharif H. (2017). The role of novel genes in CNS axon regeneration. University of Birmingham. Ph.D.

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Abstract

Unlike the peripheral nervous system, the spinal cord which forms part of the central nervous system (CNS) is unable to regenerate. Intrinsic and extrinsic environment changes following spinal cord injury are the main factors contributed to inhibit neuronal survival and axonal growth. However, manipulating the growth-relative genes in the CNS after injury can induce limited axon regeneration. In this study we demonstrate by manipulating expression of three protein molecules AMIGO3 (an amphoterin-induced gene open reading frame), RTN3 (Reticulon 3) and astrocyte elevated gene-1 (AEG-1/ also known as MTDH/LYRIC1)), where axon regeneration in the CNS is possible. Data from a microarray screen in regenerating and non-regenerating spinal cord injury models showed that low levels of AMIGO3 expression correlated with regenerating sciatic nerve (SN) and preconditioning SN+DC lesion models. Conversely, high levels of RTN3 and AEG-1 were found to be correlated with regeneration injury models. \(In\) \(vitro\) knockdown of AMIGO3 combined with neurotrophin 3 (NT3) has been shown to promote dorsal root ganglion neuron (DRGN) neurite outgrowth, and \(in\) \(vivo\) delivery of non-viral mediated shRNA/AMIGO3 plasmid to suppress AMIGO3 expression demonstrated significant DC axon regeneration. In addition, \(in\) \(vitro\) knockdown of both RTN3 and AEG-1 suppressed DRGN neurite outgrowth, demonstrating that they are required for axonal growth. The mechanisms by which AMIGO3, RTN3 and AEG-1 suppress or promote axonal regeneration is not yet known but we conclude that they play a major role in axonal regeneration and could be harnessed to promote regeneration of the CNS.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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