Alicia Hidalgo lab  School of Biosciences, University of Birmingham

 

NeuroDevelopment Group: CNS Development, Plasticity, Evolution

No canonical neurotrophin receptor homologues of the Trk family or p75 have been found in fruit-flies. Instead, Spz is a well-known ligand of Toll. The Toll receptor superfamily has universally conserved functions in innate immunity. We have found that Drosophila Toll-6 and Toll-7 are expressed in the CNS from the embryo to the adult brain, throughout the locomotor circuit and in dopaminergic neurons, and they are required for connectivity, neuronal survival and locomotion. Toll-6 and Toll-7 bind DNT1 and DNT2, and function as receptors for these neurotrophin superfamily ligands. This reveals the distinct evolution of neurotrophin signalling, shared origins of the immune and nervous systems, and unforeseen relationships between the neurotrophin and Toll protein superfamilies.

We have shown that a neurotrophin protein family formed of DNT1, DNT2 and Spz regulates cell number, connectivity and synaptogenesis also in the fruit-fly, Drosophila. This suggests that the neurotrophin family operates across animals with a centralised brain to regulate brain structure and function and supports the notion that a common mechanism underlies structure-function relationships of all brains. These findings are important to use Drosophila as a model to understand the brain and to model brain diseases.

We wish to understand what makes nervous system structure robust and reproducible. How does a brain know when to stop growing? How do cells know when a circuit is complete and ready to work? If a structure is damaged, how does the organism know what to mend and when it’s mended? We want to understand how this works in terms of cellular, genetic and molecular mechanisms. One way to probe how robust a system is, is to test its response to injury, and see whether it will repair or regenerate, or not. Understanding the underlying fundamental molecular and genetic mechanisms is essential to find out how to regenerate the damaged (e.g. spinal cord injury) or diseased nervous system (e.g. stroke, multiple sclerosis).


We have recently discovered a gene network underlying the glial regenerative response to CNS injury in Drosophila, and we are now collaborating with mammalian experts to directly test whether this gene network also operates in mammalian glia using mice - closer to human conditions.

To address questions on structural plasticity, it is essential to acquire quantitative information on cell number (e.g. the number of dying or dividing cells, neurons or glia, in different genotypes or conditions) and number of synapses. Thus we developed programmes to enable us to do exactly that, for the whole central nervous system of Drosophila embryos, larvae and the adult brain. We also developed a programme to track crawling larvae. All of our programmes were developed as ImageJ plug-ins and are freely available through our “Lab Software”tab.

Our research has been and is funded by:

Our lab aims to understand how the nervous system is formed, and how it works. Structure and function come together in the course of development, and influence each other throughout life, endowing the nervous system with plasticity. As the animal grows and nervous system volume and cell number increase, the two cell types in the nervous system - neurons and glial cells - make adjustments that modify cell division and cell survival, cell migration patterns, axonal trajectories, dendritic arbors and neural circuits. These plastic adjustments result in the robust, reproducible formation of the nervous system across individuals, and over evolutionary time, and enable the changes taking place throughout life, such as during learning and memory. Conversely, these cell interactions fail in diseases of the nervous system (e.g. neurodegeneration, psychiatric disorders and brain tumours) and upon injury (e.g. upon spinal cord injury and stroke).


We use the fruit-fly Drosophila because it is a very powerful model organism to address questions swiftly, in vivo and with single cell resolution, whilst it does not raise ethical concerns. Our approach combines genetics, molecular biology, cell culture, computational analysis, in vivo confocal microscopy in fixed specimens and in time-lapse, and behaviour. We collaborate with biochemists, structural biologists, electrophysiologists and mammalian experts.


We work within the reference of evolution, since any inference from fruit-flies to humans needs to go via the common ancestor.


We have shown that neuron-glia interactions influence axonal patterns, glial migration and cell number during axon guidance and connectivity; that neurotrophic and gliatrophic factors have fundamental functions in nervous system formation, in fruit-flies like in humans; and we have discovered a glial gene network that promotes structural robustness and plasticity in the normal animal, and repair after CNS injury.


Ultimately, our research contributes to understanding nervous system structural and developmental plasticity; brain evolution and the mechanisms underlying different brain types and behaviours; and how to repair the diseased or damaged nervous system.


We are currently pursuing the following projects:

Find out about our past contributions to neuron-glia interactions during axon guidance and the regulation of glial and neuronal cell number by neurotrophic and gliatrophic factors in Drosophila. We showed that glia are required for growth cone guidance. We showed that the gliatrophic factors Vein - a Neuregulin-like protein - and PVF - homologue of PDGF and VEGF - both maintain glial survival in flies as they do in mammals.