Chair:
Dale R. Abrahamson, PhD
Graduate Studies Director:
Douglas E. Wright, PhD
Director of
Medical Education:
George C. Enders, PhD
Email inquiries:
hallensw@kumc.edu
email: jbruses@kumc.edu
Cell-Cell interactions in synapse formation and function
The synapse is the site of functional contact between two excitable cells, and is comprised of the pre and postsynaptic terminals, and the molecular machinery required for synaptic transmission. The complexity of the synapse is highlighted by the enormous diversity of proteins and molecular mechanism required for both, the assembly of a synaptic contact, and for the physiology and regulation of neurotransmission.
The long-term goal of my research is to elucidate the cellular and molecular mechanisms that participate in the assembly of the nervous system, and my studies focus primarily on the role of cell-cell interactions mediated by surface receptors in the formation of a synaptic contact. The main questions that we are trying to address are: 1) which surface molecules are key players in the development of the synapse, 2) how these proteins transduce signals into the cell, and 3) how these signaling mechanisms influence synaptic physiology. The importance of understanding the biological rules that govern the formation of a synaptic contact is underscored by the fact that synapses are the centerpiece of neuronal communication and they become affected in a variety of neurological and mental disorders, including autism, mental retardation, schizophrenia, and Alzheimer’s disease.
One of the current focuses of the lab is the study of the role of neural-cadherin (N-cadherin) in the structural and functional organization of a synaptic contact. N-cadherin is an adhesion- receptor abundantly localized at the synapse where it contributes to the assembly of the synaptic complex by providing adhesion between synaptic membranes and organizing the underlying actin cytoskeleton. In addition, N-cadherin may participate in synaptic physiology by regulating voltage-activated calcium currents. This is important because calcium concentrations affect a variety of neuronal functions including excitability, signaling, and gene expression. Thus, the central question of this project is how N-cadherin binding transduces a signal into the neuron that leads to regulation of the activity of calcium channels and neuronal physiology. As both, the regulation of cadherin adhesion activity and signaling are affected by the binding of molecules to the N-cadherin intracellular domain, we are analyzing which binding partners are required for N-cadherin signaling activity and which down stream pathways are modulated. The elucidation of these molecular mechanisms will contribute to our understanding of how neuronal interactions participate in the establishment of neural circuits.
In addition to the studies on N-cadherin, we are currently searching for molecules which are required for the assembly of the synapse. To identify these molecules, we carried out a genome-wide search of transcripts which become highly expressed at the time synapses are starting to form. By analyzing the expression profile of these transcripts during neuronal development, and the characteristics of the proteins that they encode, we have identified distinct groups of proteins that become expressed on the neuronal surface precisely at the time the synapse is forming. To determine the role of these transcripts in synapse development, we use an in vitro cell assay in which the ability of these proteins to trigger synapse formation can be easily tested. Thereafter, the role of these proteins in synapse formation is studied in vivo by expressing wild type or mutated protein in the chick embryo using in-ovo electroporation or viral transfection. With these studies, we expect to identify molecules and mechanisms underlying this fundamental developmental process.
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The University of Kansas Medical Center