PRIZE FELLOWS 2009

Dr Juan Burrone

MRC Centre for Development Neurobiology

King's College London

Juan received his undergraduate degree in Biochemistry at the University of Bristol, U.K. He then switched to the field of neurobiology as a PhD student in Dr. Leon Lagnado’s laboratory, at the MRC Laboratory of Molecular Biology in Cambridge, U.K., where he studied the release of neurotransmitter at a large retinal synapse. Continuing with his interest in synapse physiology, he joined Prof. Venkatesh Murthy’s laboratory at Harvard University, Cambridge, USA, as a postdoctoral fellow. Juan’s work in the Murthy lab expanded to include both presynaptic neurotransmitter release and long-term forms of synaptic plasticity. Since 2005 he has been a group leader at the MRC Centre for Developmental Neurobiology in King’s College London, U.K.

One of the main goals of our lab is to understand how synaptic connections, the sites of communication between neurons, are established. The transfer of information at the synapse is governed by the release of neurotransmitter from a presynaptic terminal and the subsequent activation of postsynaptic receptors. We are interested in following the maturation, both structurally and functionally, of the presynaptic terminal during circuit development, as neurons extend axons to form synaptic connections with other neurons. In addition, the number and strength of synaptic contacts must also be tightly controlled, a process which is thought to be modulated by neuronal activity. We will explore the evolution of a synapse from its early origins during growth cone extension, to the moment of synapse formation and maturation and establish how neuronal activity influences these events.

 There are two aspects of this presynaptic narrative which we are interested in understanding: 1- the maturation of neurotransmitter release at a presynaptic terminal and 2- the role that neuronal activity plays during synaptogenesis. We are currently tackling the first question by using genetically-encoded fluorescent probes that report vesicle cycling in individual synapses. Using a newly developed probe in our lab, we can follow vesicle dynamics in presynaptic terminals as synapses form and mature. In addition, we can also characterize the functional properties of the postsynaptic compartments, as it receives presynaptic inputs, to understand how both sides of the synapse mature in parallel. To address the second question we use genetically-encoded modulators of neuronal activity that allow precise control of neuronal firing with single-cell resolution. Our previous studies employed modulators of activity to silence an individual neuron in a network, uncovering competitive forms of synaptic plasticity during development. In the future, we plan to use new technology to go beyond the resolution of a single cell and alter neuronal activity in subcellular compartments to understand the mechanisms behind activity-dependent synapse remodelling. Our aim is to exploit these new molecular and technological advances to understand how synaptic connections between neurons are established and how neuronal activity sculpts the number and strength of synapses in a network. This work may have important implications for our understanding of neurodevelopmental diseases, many of which are thought to result from abnormal synaptic development.

Dr Andrew Jackson

MRC Human Genetics Unit

Institute of Genetics & Molecular Medicine

Edinburgh

Andrew studied Medicine at Newcastle University and did his PhD on the molecular genetics of primary microcephaly with Geoff Woods and Alex Markham at the Molecular Medicine Unit in Leeds.   His postdoctoral work, funded by an MRC Clinician Fellowship continued in Leeds, with time also spent in Sheffield in Philip Ingham’s Centre for Developmental Genetics, before he moved to Edinburgh in 2005 to establish a group in the MRC Human Genetics Unit, where he is currently an MRC Senior Clinical Fellow.  He is also an honorary Consultant Clinical Geneticist with a subspecialty interest in neurogenetics.   

His research strategy is to identify novel genes for monogenic neurological disorders and then study the function of the proteins they encode. Utilising cell biology and model organisms he hopes to gain novel insights into basic biological mechanisms and disease pathogenesis. His work currently focuses on two areas: firstly, disorders of reduced brain size (primary microcephaly and microcephalic dwarfism), and secondly autoimmune disorders of the brain.

Primary microcephaly and microcephalic dwarfism are disorders of markedly reduced brain size, with brain volumes similar to those of early hominids.  Recently, with his collaborators Penny Jeggo and Mark O’Driscoll, his group has identified mutations in Pericentrin, a gene encoding a structural centrosomal protein, in Seckel syndrome ( a form of microcephalic dwarfism). Surprisingly, they also established that it is a component of the ATR-dependant damage response pathway. This suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function, may act in  common developmental pathways determining human brain size.  Currently work is ongoing to identify further genes for microcephalic dwarfism with the intention of identifying other novel components of the ATR pathway, and defining cellular pathways important for determining brain size. 

Aicardi-Goutières syndrome (AGS) is a childhood-onset auto-inflammatory disorder of the brain that mimics congenital viral infection.  It also has clinical and immunological similarities with common autoimmune diseases such as SLE.  The Jackson lab has been involved in identifying four genes for this autosomal recessive disorder that encode two nucleases, RibonucleaseH2 and TREX1. With its now defined molecular basis, AGS provides an important human model for nucleic-acid mediated inflammation, and lab members are currently studying the cellular biology of Ribonuclease H2, defining the nucleic acids that accumulate as the consequence of its dysfunction and establishing in vitro and in vivo how these nucleic acids stimulate an autoimmune response.

Dr Grant Stewart

CRUK Institute for Cancer Studies

University of Birmingham

I received my first degree in Cellular and Molecular Pathology at the University of Bristol (1996). I subsequently joined the laboratory of Professor Malcolm Taylor at the University of Birmingham to do a Ph.D. studying the heterogeneity of the chromosomal instability syndrome, Ataxia-Telangiectasia (A-T), and the role of the ATM (Ataxia-Telangiectasia Mutated) gene in sporadic leukaemia. During the course of my Ph.D., I identified mutations in the DNA double strand break (DSB) gene, hMRE11, in patients apparently with A-T. This led to the recognition of a new disorder similar to A-T (A-T-like disorder or ATLD), firmly establishing a link between the hMre11 DSB repair complex, progressive neurological defects and ATM.

To continue my growing interest in the cellular response to DNA damage, I moved in 2002, with a European Molecular Biology Organisation (EMBO) Long Term Fellowship, to the laboratory of Professor Stephen Elledge at Baylor College of Medicine (Houston, Texas). Whilst at Baylor, I identified a novel DNA double strand break repair protein called Mediator of DNA Damage Checkpoint 1 (MDC1) and demonstrated it played a role in recruiting other DSB responsive proteins to the sites of DNA breaks to facilitate repair and cell cycle checkpoint activation. 

In 2005 I moved back to the University of Birmingham with a CR-UK Career Development Fellowship to start up my own laboratory investigating the function of the DNA DSB repair proteins, MDC1 and 53BP1, during the cellular response to DNA damage and also how defects in pathways controlled by these proteins contribute to human disease and tumourigenesis. Recently my group has identified a novel human immunodeficiency syndrome associated with defective repair of DNA DSBs called RIDDLE syndrome. ‘RIDDLE’ is an acronym describing its common clinical features: Radiosensitivity, ImmunoDeficiency, Dysmorphic facial features and LEarning difficulties. Through collaboration we were able to identify the gene mutated in RIDDLE syndrome as RNF168 and that the encoded protein facilitates the recruitment of DSB repair proteins, such as 53BP1 and BRCA1, to sites of DNA damage by promoting relaxation of the chromatin structure surrounding the break.

Despite these findings, very little is known about the function of RNF168 during the cellular response to DNA DSBs and how defects in this pathway contribute to human immunodeficiency. Therefore our aims are to 1). Determine whether RNF168 plays a role in DNA repair processes specifically associated with immune system development, 2). Identify and characterise novel RNF168 binding proteins to gain insight into how RNF168 is regulated and 3). Assess whether functions to coordinate repair of DNA lesions in addition to DNA DSBs e.g. damage caused by ultra-violet (UV) light and DNA cross-linking agents. In the long-term, my aim is to understand the role of both RNF168 and other new components of the cellular response to DNA damage and their potential involvement in cancer development.