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The role of APRIL in the development of the peripheral nervous system

White, Matthew 2013. The role of APRIL in the development of the peripheral nervous system. PhD Thesis, Cardiff University.
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Critical to the development of the peripheral nervous system is the regulation of the growth and survival of neurons during the phase of target field innervation. Neurons extend axons towards their target tissues and branch extensively forming complete functional synaptic connections by the end of development. This study has revealed the first known role for the tumor necrosis superfamily (TNF) member a proliferation inducing ligand (APRIL) in the development of the nervous system. Neurons of the mouse superior cervical ganglion (SCG) were chosen for study as an excellent model of peripheral development. These neurons can be easily dissected and cultured to study their growth and survival under controlled experimental conditions. The target fields innervated by this population of neurons are clearly defined, offering the opportunity to study final target field innervation, meaning this population offers excellent experimental potential. This study demonstrated for the first time that the mRNA transcripts for the TNF superfamily member APRIL and its receptors B cell maturation antigen (BCMA) and transmembrane activator and cycophylin interactor (TACI) are expressed in the SCG and target fields during the development of these neurons at a time when they are innervating their peripheral targets. Investigation of protein expression demonstrated that these neurons express this ligand and its receptors, localised to the cells themselves as opposed to projections innervating distal target fields. Functional analysis of the role of APRIL, BCMA and TACI on the growth and survival of SCG neurons in vitro demonstrated that, in the presence of nerve growth factor (NGF) the principal neurotrophin acting on these cells, either treatment with recombinant APRIL or a function blocking antibody to APRIL, enhance the growth of these neurons independent of survival. This effect is clear over a wide developmental window from embryonic day 16 to post natal day three. The ability of recombinant APRIL to enhance this growth requires the presence of a putative heparin sulfate binding domain. In addition to the activity of these factors, function blocking antibodies against the receptors BCMA and TACI also enhance NGF promoted neurite growth as do soluble recombinant forms of the receptors. Interaction with APRIL signalling acts to promote the growth of SCG neurons in culture. This enhancement of growth requires the activity of mitogen-activated protein kinase kinase and Phosphatidylinositide 3-kinase. Neurons cultured from APRIL null mice grow larger than their wild type counterparts in the presence of NGF. Two target fields innervated by these neurons, the submandibular salivary gland and nasal mucosa are hyperinnervated at post natal day five in APRIL null mice. This phenotype is not evident by post natal day 10 and so points to a transient, but significant, increase in target field innervation.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Biosciences
Subjects: Q Science > QH Natural history > QH301 Biology
Date of First Compliant Deposit: 30 March 2016
Last Modified: 10 Oct 2017 15:33

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