Regulation of neuronal number and connectivity by neurotrophins via Toll receptors in the visual system of Drosophila

Alshamsi, Naser (2024). Regulation of neuronal number and connectivity by neurotrophins via Toll receptors in the visual system of Drosophila. University of Birmingham. Ph.D.

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Abstract

As the brain grows, neuronal number is coupled to the emergence of neural circuits ensuring correct connectivity conducive to normal behaviour. Across animals, neurons are produced in excess, neurotrophic growth factors are secreted in limiting amounts and only neurons that receive trophic support are maintained alive (Levi-Montalcini, 1987). In mammals, this is regulated by neurotrophin ligands function via tyrosine-kinase Trk and TNF-family p75 receptors. Drosophila neurotrophins (DNTs) belong to the Spätzle (Spz), paralogue group that function via Toll receptors instead. Intriguingly, the link between these major protein families could be evolutionarily conserved, but still remains unexplored in mammals. DNTs and Tolls regulate cell survival during axon guidance in the Drosophila embryo, and neuronal survival in the adult brain (Zhu et al 2008; McIlory et al 2013; Li et al 2020). However, the optic lobe is the ideal context to further probe neurotrophism in Drosophila : vast number of neurons die naturally during pupal development and connectivity patterns in the visual system are well known. The data show that DNTs and Tolls are expressed dynamically during pupal visual system development, in distinct spatial profiles. Interfering with the functions of DNT-2/spz-5 and DNT-3/spz-3 can either prevent or promote neuronal survival. Data suggest that this is mediated via Toll-2, -6 and -8 as the effects can be rescued with epistasis. Furthermore, the alterations in neuronal number correlate with altered dendrite and axonal patterns and connectivity. Moreover, DNTs can promiscuously bind multiple Toll receptors, confirming previous reports (Foldi et 2017), and implying that this molecular mechanism is unlikely to function in cell-cell contact recognition synaptic matching. Altogether, the data support a function for DNTs and Tolls in the control of cell number and connectivity during visual system development that supports the evolutionary conservation of neurotrophism as a fundamental principle of nervous system development.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):