Neurons are specialised cells in our body that have long extensions allowing them to form connections (called synapses) with other neurons, leading to the establishment of neural circuits. The main function of neural circuits is to conduct signals that coordinate our bodily functions, thoughts, sensations, and perceptions of the world. Overall, neural circuit function and ultimately behaviour depend on the precise formation of synaptic connections. Hence, changes in the way neurons are wired during development can lead to neurodevelopmental disorders such as autism spectrum disorder, intellectual disability, and Schizophrenia. Moreover, failure to properly maintain synapses throughout life often results in neurodegenerative conditions such as Alzheimer’s and motor neuron disease.

The human brain contains approximately 86 billion neurons and a 1,000 trillion synapses. This indicates the staggering complexity in the way neuron wiring is established during development. To understand the development of a functional nervous system, our lab uses zebrafish as a vertebrate genetic model system. We are interested in elucidating fundamental molecular and cellular mechanisms that are essential for neural circuit formation during developmental periods, how neural connections are maintained throughout life, and how such processes are mis-regulated in certain neurological disease conditions. There are three areas of research in the lab:

(i) linking neuronal structure with function.

(ii) extra-nuclear RNA splicing regulators in dendrites.

(iii) understanding human disease.

Linking neuronal structure with function:

Neural circuit function and ultimately animal behaviour depend on the precise formation of synaptic connections in the brain. Within the brain, morphologically distinct subtypes of neurons make region- and layer-specific innervations to form synapses with their target neurons. An important question in neuroscience is how these subtype specific connections form and what behaviours they control. To shed light into the mechanisms that specify subtype specific connections in the brain, we are molecularly defining classes of neurons through single-cell RNA sequencing. This will enable us to identify genes that are uniquely expressed in distinct classes of neurons. Using CRISPR/cas9 and transgenesis tools, individual subtypes of neurons are marked with the aim to characterise their morphologies, neurotransmitter phenotypes, functional response properties, and ultimately reveal novel connectivity mechanisms.

Extra-nuclear RNA splicing regulators in dendrites:

Another area of research in the lab is focused on investigating the extra-nuclear activities of RNA splicing proteins during neural wiring. We have recently shown that U1-70K/SNRNP70, a major spliceosome protein, localises inside ribonucleoprotein complexes within axons and regulates the establishment of neuromuscular connectivity. Our findings indicate that cytoplasmic SNRNP70 modulates the axonal transcriptome. We are now exploring the mechanisms by which local transcriptome composition is regulated by RNA splicing regulators and how such local mRNA processing steps influence the establishment and maintenance of neuronal connectivity. Moreover, many of the RNA splicing proteins found in axons thus far can also aggregate and form insoluble complexes in the cell’s cytoplasm, and that these complexes can interfere with the function of a neuron, eventually causing the neuron to lose function and degenerate. Now we know these types of molecules have a function outside the nucleus, another line of research in our lab focuses on understanding how these disease-causing aggregates interfere with the function of these proteins not only in the nucleus but also in the cytoplasm, and what role they play in the breakdown of neurons.

Understanding human disease:

Many genes important for neuronal development are also linked to neurological diseases such as neurodevelopmental disorders and neurodegeneration. As a first step in understanding human disease, we try to determine the function of disease-related genes in the nervous system. KIF1A, a member of the kinesin-3 family, is a neuronal-specific gene found throughout the nervous system that has been linked to disease. KIF1A is responsible for the anterograde transport of synaptic vesicle proteins to axon terminals as well as other diverse cargos important for neuron growth and function, such as neuropeptides and neurotrophic factors. Our work aims to examine the function of KIF1A during the establishment of functional neural circuits in vivo, where all cellular components are present. Moreover, we are interested in understanding the relative contribution of pre- and post-synaptic KIF1A for neural circuit function. In humans, mutations inside the KIF1A gene have been linked to a rare neurological condition with a range of clinical symptoms, including neural atrophy, epilepsy, visual impairment, and spastic paraplegia. We are now in the process of generating zebrafish genetic models for human KIF1A mutations that we can use to understand the effects these mutations have on the developing brain. Eventually, we plan to use these genetic models for small molecule drug screening to identify modifiers of the disease.

Broad technical expertise in our lab:

- Genetic alterations using CRISPR/cas9 and transgenesis techniques

- Grafting/transplantation of cells or tissues

- Transcriptomic profiling of cells

- Live imaging techniques

- Behaviour analysis to study circuit function

- Primary neuron cultures  

We are always open to students interested in neuronal development and connectivity. PhD funded projects in the lab will appear here when become available. Postdocs interested in joining our lab are also welcomed. If interested, please contact me well in advance for an informal discussion.

Nikolas Nikolaou's education role spans across undergraduate (UG) and postgraduate degrees. He delivers lectures on Developmental Genetics, Neuroscience, and Developmental Neurobiology to UG year 2 and final year students in Biomedical Sciences, Biochemistry, Biology, and Natural Science course programmes. He supervises research projects for final year undergraduates and offers MSc lab projects. He supervises on average 2 PhD students working in his lab. He is also an academic tutor, supporting directly 20-30 students each year.