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Séminaire - Joris de Wit"Control of Neural Circuit Development by Leucine-Rich Repeat Containing Proteins"

Abstract :

The nervous system consists of billions of neurons that are precisely connected into neural circuits. The organization of these specific connections emerges from sequential developmental events that include target selection and synapse formation. These processes critically rely on cell-cell recognition and communication mediated by cell-surface ligands and receptors. The complexity of the ligand-receptor interactions involved is only beginning to be understood. Recent studies have revealed key roles for leucine-rich repeat (LRR) domain-containing proteins in organizing neural connectivity. Their versatile LRR domains serve as key sites for interactions with a wide diversity of binding partners on the cell surface. In this talk, I will focus on a few examples of LRR proteins in organizing precise synaptic connectivity in the vertebrate brain and discuss their role in the development and disorders of neural circuits.

The brain is the last great frontier - Joris de Wit , more..

Selected publications

NGL-2 Regulates Input-Specific Synapse Development in CA1 Pyramidal Neurons
Denardo L, De Wit J, Otto-Hitt S, Ghosh A
NEURON, 76, 762-75, 2012

FLRT proteins are endogenous latrophilin ligands and regulate excitatory synapse development
O'sullivan m, De Wit J, Savas J, Comoletti D, Otto-Hitt S, Yates J, Ghosh A
NEURON, 73, 903-10, 2012

Role of leucine-rich repeat proteins in the development and function of neural circuits
De Wit J, Hong W, Luo L, Ghosh A
Annual Review of Cell and Developmental Biology, 27, 697-729, 2011

Molecular mechanisms of synaptic specificity in developing neural circuits
Williams M, De Wit J, Ghosh ANEURON, 68, 9-18, 2010

LRRTM2 interacts with Neurexin1 and regulates excitatory synapse formation
De Wit J, Sylwestrak E, O'sullivan m, Otto S, Tiglio K, Savas J, Yates J, Comoletti D, Taylor P, Ghosh ANEURON, 64, 799-806, 2009

Scientific focus :

Our brain is made up of billions of neurons that are precisely connected into neural circuits, forming an immensely complex network that encodes our thoughts, memories and personalities. Cognitive disorders such as autism and schizophrenia are thought to somehow result from changes in the connectivity of this network. Our lab aims to unravel the molecular mechanisms that control neuronal connectivity in developing circuits, and determine how perturbations in this process affect cognitive function.

During brain development, neurons connect with specific target neurons through highly specialized cell-cell contacts called synapses. Synapses are central to the functioning of the brain, and a loss of synaptic connectivity is thought to underlie many cognitive disorders. Understanding the molecular mechanisms that control the formation and maintenance of synaptic connections is therefore essential in order to gain insight into these disorders. However, many fundamental questions about circuit formation are still unanswered. How do neurons recognize their appropriate partners? How are nascent cell-cell contacts differentiated into functional synapses? And how is it that synapses between different types of neurons are structurally and functionally distinct?  

To address these questions, we use a combination of proteomics, neuronal cell culture, conditional mouse genetics, viral vectors, electrophysiology and anatomical technques. With this approach, we aim to obtain new insights into the molecular mechanisms that establish precise synaptic connectivity under normal and pathological conditions. Ultimately, these insights will guide the development of new strategies for improved diagnostics and treatment.