Nervous system developmental and structural plasticity: neurodegeneration, regeneration and repair

Our lab aims to understand how the nervous system is formed, how it works and how it can be repaired after damage. 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 migration patterns, axonal trajectories, dendritic branches, cell division and cell survival. Plastic adjustments occur also with synaptic function and can affect axonal branches, dendritic trees and synaptic structure. These plastic adjustments result in the robust, reproducible formation of the nervous system across individuals, they enable the brain to adapt to environmental changes and experience, and decay with ageing. Stimuli like enriched environments, neuronal activity and voluntary exercise increase brain plasticity, and conversely, loss of structural plasticity correlates with many brain diseases, from neurodegenerative (e.g. Alzheimer’s disease, Parkinson’ disease) to mental health and psychiatric disorders. Understanding how to increase structural plasticity can help enhance brain health, combat brain tumours and promote regeneration and repair following injury, damage (e.g. stroke) and disease. 

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. Our approach combines genetics, molecular biology, cell culture, computational analysis and in vivo confocal microscopy in fixed specimens and in time-lapse.
We have long-term collaborations with biochemists and structural biologist Prof. N.J. Gay, Univerity of Cambridge, and imaging specialist Dr Manuel Forero, University of Ibague, Colombia. It is important to further test Drosophila findings in mammals, which we do with collaborators using mice and rats as model organisms (e.g. Prof. A. Logan, IBR Birmingham and Dr F. Matsuzaki, Riken, Japan).

We have recently discovered: 

1. Drosophila Neurotrophins (DNTs) and the Drosophila neurotrophin system: 
a neurotrophin protein family in Drosophila formed of DNT1, DNT2 and Spz regulate neuronal cell number, connectivity and synaptogenesis. This demonstrated conserved structure and function of the neurotrophin super-family from flies to humans. The findings support the notion that a common mechanism underlies the origin and function of all brains in evolution and that there are fundamental aspects in the way brain structure and function are linked, in fruit-flies and humans. These findings are important to use Drosophila as a model to understand the brain and to model brain diseases. 

2. Toll-receptors as neurotrophin receptors in the CNS
receptors for the DNTs belong to the Toll receptor super-family, revealing an unanticipated link between the neurotorphin and Toll-receptor families in the CNS. Whereas Toll receptors in flies and Toll-Like-Receptors (TLRs) in mammals have universal functions in innate immunity, we found that Toll-6 and Toll-7 in flies function as neurotrophin receptors to regulate neuronal number and targeting, and behaviour. 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 super-families. We shwed that in the CNS, Tolls can regulate both cell survival and cell death: whether a neuron lives or dies depends on the ligand it receives and its cleavage state; the Toll or combination of Tolls it expresses; and the available downstream effectors. Our findings revealed that Tolls regulate cell number plasticity in the CNS, through a previously unforeseen mechanism.

4. A novel mechanism of structural synaptic plasticity involving Kinase-less Trk family Kek receptors

There are no canonical full-length tyrosine kinase Trk receptors in Drosophila. This is surprising as synaptic plasticity, learning and long-term memory are known to depend on the kinase function of TrkB and these processes occur in the fly. Paradoxically, full-length TrkB is virtually absent from the adult mammalian brain, and the most abundant isoforms are those lacking the kinase domain instead.  Importantly, alterations in kinase-less truncated Trks are linked to severe depression, mental health disorders and suicite. Amazingly, in Drosophila, Trk-family receptors are found in the Kekkons, which share the extracellular ligand-binding domains with Trks, but lack the intracellular tyrosine kinase. We have found that Kek-6 functions presynaptically as a receptor for DNT2. DNT2 is a retrograde factor, and Kek-6 regulates synaptic structural plasticity by activating CaMKII. Furthermore, Kek-6 and Toll-6 (the other DNT2 receptor) interact, and together form a receptor complex that regulates axonal branching and complexity, bouton formation and synaptic structure. Our work has revealed a novel mechanism of structural synaptic plasticity involving Tolls and kinase-less trk receptors, that could also operate in the human brain.

Altogether, we have found a Drosophila neurotrophin system formed of DNTs/Spz-family ligands, Toll receptors and kinase-less Kek Trk-family receptors. 

4. A gene network for central nervous system regeneration and repair 
Glial cells have regenerative potential and investigating glial functions is key to understand how to promote CNS repair following damage. Injury to the spinal cord or brain induces a glial regenerative response (GRR) that results in glial proliferation followed by differentiation and axonal re-enwrapment, and limited recovery of behaviour. This response is conserved across the animals – from cockroach and flies to fish, rodents and humans - and correlates with the remitting phases of multiple sclerosis, implying an underlying genetic mechanism exists. Using the fruit-fly as a model organism, we pioneered novel methods to investigate injury and CNS regeneration and repair using fruit-flies, and we a discovered a gene network underlying the GRR. This involves the genes Notch and kon-tiki/NG2 that promote glial proliferation, and Pros/Prox-1 that promotes glial differentiation. We have shown that we can manipulate this gene network to prevent or promote glial regeneration and injury repair. In collaboration with mammalian experts, we showed that this gene network is also conserved in the mouse. We are expanding this gene network to discover more genes and novel mechanisms in fruit-flies, that ultimately could be used for stem cell reprogramming and regenerative biology (e.g. cell transplantations), to promote regeneration and repair of the nervous system (e.g. spinal cord) also in humans.

5. Research in Imaging. 
To address questions on structural plasticity, regeneration and repair, 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 and walking adult flies. All of our programmes were developed as ImageJ plug-ins and are freely available through our lab web-page. 

FUNDING: Research by the Hidalgo lab is, and has over many years been, funded by: multiple The Wellcome Trust and BBRSC Project Grants, four EU Marie Curie-Sklodowska Fellowships, MRC-Career Establishment Grant, The Royal Society and EMBO, and PhD studentships from the BBSRC, MRC, the Government of Brunei, CAPES/Science Without Borders of Brazil and The Darwin Trust. We are very grateful to our funders.

PUBLICATIONS: Our research has resulted in publications in journals such as Development, Developmental Cell, EMBO Journal, PLoS One, PLoS Genetics, PLoS Biology, Journal of Cell Biology and Nature Neuroscience.

I grew up in Madrid, Spain, and carried out my first degree in Biological Sciences at the Universidad Complutense in Madrid, graduating in 1986. I obtained my PhD (DPhil) from the University of Oxford (Madgalen College) in 1990, on Drosophila developmental genetics and supervised by Prof. Phil W. Ingham. I subsequently (1990-1992) obtained a post-doctoral fellowship from the Spanish Ministry of Science and Education to do a post-doctoral period with Prof Antonio García-Bellido, at the Universidad Autónoma de Madrid, working on the control of growth and form in Drosophila development. I returned to UK with a Marie Curie Human Capital and Mobility Fellowship to do a second post-doc with Prof Andrea H. Brand at the Wellcome/CR-UK Institute, University of Cambridge (1993-1997). After this, I was awarded a Wellcome Trust Research Career Development Fellowship to establish my independent research group at the Department of Genetics, University of Cambridge (1997-2002). Here, I established my line of research into neuron-glia interactions during nervous system development. In 2001 I received an EMBO Young Investigator Award for my achievements as a young group leader. In 2002, I moved to the School of Biosciences, University of Birmingham, appointed Senior Lecturer, and where I consolidated my research into nervous system development using Drosophila. I was promoted for Reader in 2012 and awarded a Fellowship of the Royal Society of Biology in 2014.

1990 DPhil (i.e. PhD) in Developmental Genetics, University of Oxford, Magdalen College, UK

1986  Licenciada en Ciencias Biologicas (equivalent to BSc in Biological Sciences), Universidad Complutense de Madrid, Spain