TNF superfamily forward and reverse signalling in neural development. (360G-Wellcome-103852_Z_14_Z)

Our work over the past 5 years has revealed that multiple members of the TNFSFare selective positive or negative regulators of axon growth throughout the developing mousenervous system. Two very recent key discoveries arising from this work underpin the proposed programme and take our research in exciting new directions that will significantly advance our understanding of how the nervous system gets wired up in development. First, we discovered that TNFR1 expressed in sympathetic target tissues activates reverse signalingvia membrane integrated TNFalpha expressed by sympathetic axons as they ramify within thesetissues, promoting axon growth and tissue innervation (Kisiswa et al., Nature Neuroscience, 2013, 16:865-873). This discovery raises a host of interesting and important questions about the cell biology and mechanism of action of TNFalpha reverse signalling and why this has evolved to regulate axon growth in the developing nervous system. It also raises the question of how extensively reverse signaling operates within the TNFSF in the nervous system and what is the balance between forward and reverse signaling in the regulation of neural process growth. Second, we discovered that certain TNFSF signaling loops that either promote or inhibit axon growth are very sensitive to the ambient neurotrophin concentration. This reveals the existence of unsuspected feedback loops that selectively modulate the response of neurons to the neurite growth-promoting effects of neurotrophins. This raises questions about how, where and when these feedback loops operate and what it their significance for establishing patterns of innervation in vivo.