Neurotrophins in Development and Disease of the Nervous System
Laura Cassels, Xinsheng Nan, Hayley Dingsdale and Yves-Alain Barde
School of Biosciences, Cardiff University, Cardiff UK
Neurotrophins are secretory proteins encoded by four related genes in mice and humans. They promote the survival of specific populations of neurons during the development of the peripheral nervous system by activating tyrosine kinase receptors of the Trk family. Nerve growth factor (NGF) was discovered three decades before the other neurotrophins, allowing its mode of action to be investigated in detail. Tissues innervated by NGF-dependent neurons were shown to secrete limiting amounts of NGF, explaining how target tissues regulate their own degree of innervation. However, the extent to which this appealing model can also be applied to brain-derived neurotrophic factor (BDNF) is less clear. In particular, there is not much convincing evidence that in the central nervous system (CNS), endogenous BDNF is localised in post-synaptic sites of BDNF-responsive axon terminals. In addition, the Bdnf gene is expressed by large populations of excitatory neurons, including BDNF-responsive neurons in the peripheral nervous system. This is not the case for NGF which opens the possibility for additional mode of actions for BDNF, including autocrine and paracrine mechanisms. To explore this further, we recently engineered mice expressing the NGF and BDNF receptors TrkA and TrkB in all cells, starting from the earliest stages of development. TrkA overexpression led to a phenotype indistinguishable from that observed with Ngf-/- animals, including early post-natal death. This result is in line with the target- derived mode of action of NGF and can be explained by the sequestration of NGF preventing its interaction with endogenous neuronal TrkA. By contrast, animals overexpressing TrkB were viable and fertile, unlike what has been observed with Bdnf-/- animals. Detailed analyses of cranial sensory ganglia revealed decreased numbers of neurons in BDNF-responsive ganglia, as predicted by the target-derived model. However, the prolonged postnatal survival of these animals suggest that additional, BDNF- mediated autocrine or paracrine mechanisms play an essential role during development and preserve functionalities that are lost in Bdnf-/- animals.
Much of the current interest in BDNF relates to its role in the adult CNS, in particular in synaptic plasticity and in the dysfunction of the nervous system. Whilst the mouse remains the main experimental model, it is of note that there are significant differences between mice and primates with regard to the distribution of BDNF. In primates, circulating platelets contain large quantities of BDNF and we found that human, but not mouse megakaryocytes transcribe the BDNF gene and generate a pattern of transcripts similar to neurons. Megakaryocytes are the source of BDNF in human blood and serum where the levels correlate with a number of neurological conditions. As platelets typically release their content after lesion, a process that may help tissue and nerve regeneration, we recently generated a new mouse model allowing a rigorous test of the possibility that blood-derived BDNF may play a role after lesion of the nervous system.