Specificity of neurotrophins in the nervous system : a genetic approach to determine receptor engagement by neurotrophins

The classical neurotrophic factor hypothesis describes the neurotrophins as retrograde signalling factors supporting the survival of postmitotic neurons during the development. Knock-out mice for the neurotrophins and/or their receptors have been generated and their analyses gave new insights in the temporal expression and particular functions of these factors during development. Despite partially overlapping expression of neurotrophins and Trk receptor in both the central and peripheral nervous system, the different knock-outs display distinct phenotypes, demonstrating diverse and specific roles of the neurotrophins. Further analysis showed that several neurotrophins can function as survival factors for the same neurons, indicating a potential for the neurotrophins to display compensatory effects. Further comparison of the loss of neuronal numbers between neurotrophin and Trk receptor knock-outs have suggested a role for NT3 signalling through its non-preferred receptors, TrkA and TrkB.

In this thesis the specificity and selective roles of BDNF and NT3 in the peripheral and central nervous system have been analysed. In order to analyse this, the coding part of the BDNF gene has been replaced by NT3, in genetically modified mice (BDNNT3/NT3). Analysis of the nervous system revealed striking differences in the ability of NT3 to replace BDNF. We conclude that there is no general mechanism by which neurotrophin specificity is attained and the specificity of neurotrophin signalling is set by several factors, which are dependent on the cellular system studied. These factors include a spatial and temporal expression of ligands and receptors and the activation of diverse intracellular pathways by different Trk receptors within the same neuronal population.

Finally, we also investigated the ability of NT3 to signal through non-preferred receptors in vivo. We see that there is a high degree of receptor specificity between neurotrophins and their cognate receptors in vivo.

List of scientific papers

I. Agerman K, Hjerling-Leffler J, Blanchard MP, Scarfone E, Canlon B, Nosrat C, Ernfors P. (2003). BDNF gene replacement reveals multiple mechanisms for establishing neurotrophin specificity during sensory nervous system development. Development. 130(8):1479-91.
https://pubmed.ncbi.nlm.nih.gov/12620975

II. Agerman K, Ernfors P. (2003). Differential influence of BDNF and NT3 on the expression of calcium binding proteins and neuropeptide Y in vivo. Neuroreport. 14(17):2183-7.
https://pubmed.ncbi.nlm.nih.gov/14625444

III. Agerman K, Harkany T, Dobszay MB, Minichiello L, Ernfors P. (2004). BDNF signalling through TrkB controls dendritic growth and parvalbumin expression in the olfactory bulb. [Manuscript]

IV. Agerman K, Stenqvist A, Minichiello L, Ernfors P. (2004). A non-promiscuous selective signalling of NT3 through TrkC in vivo. [Manuscript]