TNF superfamily and neurotrophin signalling differentially regulate paravertebral and prevertebral development in the sympathetic nervous system

Calhan, Osman Yipkin 2020. TNF superfamily and neurotrophin signalling differentially regulate paravertebral and prevertebral development in the sympathetic nervous system. PhD Thesis, Cardiff University. Item availability restricted.

Preview	PDF - Accepted Post-Print Version Download (86MB) | Preview
	PDF (Cardiff University Electronic Publication Form.) - Supplemental Material Restricted to Repository staff only Download (223kB)

Abstract

The sympathetic nervous system (SNS) has two distinct divisions: paravertebral and prevertebral. Previous work on the well-characterised and relatively accessible superior cervical ganglia (SCG, a paravertebral model), discovered a significant role for tumour necrosis factor (TNF) superfamily members in SNS development. The most intriguing were TNFR1-promoted TNF-α-mediated reverse signalling, and CD40-activated CD40L-mediated reverse signalling, identified as major physiological regulators of neurite outgrowth. This thesis asked whether these TNF signalling mechanisms function universally throughout the SNS, or differ across the two divisions. The innervation density of prevertebral targets (spleen, kidney, and stomach) from Tnf-, Tnfrsf1a-, and Cd40-deficient mice was investigated. In addition, the mechanisms underlying TNF signalling were compared between SCG, and coeliac and superior mesenteric ganglia (prevertebral ganglia; PVG), used here as a prevertebral model. TNF-α-reverse signalling only enhanced innervation density of paravertebral, but not prevertebral, targets. Similarly, CD40L-reverse signalling suppressed innervation of prevertebral targets, opposite to that seen in paravertebral targets. These in vivo differences paralleled in vitro findings. Whereas TNF-α-reverse signalling enhanced neurite outgrowth in SCG neurons, PVG neurons only responded to TNF-α-forward signalling. Similarly, whereas CD40L-reverse signalling enhanced neurite outgrowth of SCG neurons, this pathway suppressed PVG neurite outgrowth. These substantial differences between the two SNS divisions led to further investigations into more fundamental signalling, the neurotrophins. Nerve growth factor (NGF) and neurotrophic factor 3 (NT-3) increased neurite outgrowth of SCG and PVG neurons in a concentration-dependent manner. However, SCG neurons were significantly more responsive to NGF and NT-3 than PVG neurons. Surprisingly, these neurotrophins had no differential effects on cell survival between SCG and PVG neurons. Data here suggest that PVG and SCG neurons differ substantially in their response to both TNF and neurotrophin signalling during SNS development. Thus, future research should consider also including the prevertebral division in the study of the developing SNS.

Item Type:	Thesis (PhD)
Date Type:	Completion
Status:	Unpublished
Schools:	Biosciences
Subjects:	Q Science > Q Science (General)
Date of First Compliant Deposit:	14 April 2021
Last Modified:	10 Nov 2021 02:09
URI:	https://orca.cardiff.ac.uk/id/eprint/140486

Actions (repository staff only)

Edit Item