Barbara Ranscht

Barbara Ranscht, Ph.D.[La Jolla]

  • Research

    Dr. Ranscht studies the molecular basis of cell-cell communication in the nervous- and cardiovascular system.

  • Biography

    Barbara Ranscht earned her Ph.D. in Cell Biology/Developmental Neurobiology from the University of Tübingen, Germany in 1981.

Barbara Ranscht's Research Focus

Neurodegenerative and Neuromuscular Diseases, Multiple Sclerosis, Nervous System Injury, Metabolic Syndrome, Cardiovascular Diseases

The human brain contains approximately one trillion nerve cells that are wired into functional circuits that control cognitive and vital functions. Dr. Ranscht’s research focuses on understanding how this intricate network of selective nerve connections is generated in developing embryos. During development, nerve cells extend processes that navigate along stereotyped pathways to reach their targets – other nerve cells, muscle or glands – with which they communicate through specialized contacts or synapses. To navigate and connect to the correct target, a neuron must recognize guidance cues in its environment. Dr. Ranscht’s laboratory studies the molecular nature of such cues. The knowledge generated from this work will be useful to design compounds that permit the regeneration and correct reconnection of nerve fibers after injury or trauma.
 

Barbara Ranscht's Research Report

Barbara Ranscht

Establishment of Axon Patterns in Developing Embryos

The focus of our research is to understand the molecular mechanisms of axon guidance and target recognition in the developing vertebrate nervous system. Our laboratory uses biochemical, embryological and molecular genetic approaches to study the molecular interactions and functions of cell recognition molecules in these processes.

Current Projects: We are interested in the cellular interactions mediated by contactin, a neuronal glycosylphosphatidylinositol (GPI) -anchored cell recognition molecule of the immunoglobulin gene superfamily. We hypothesize that contactin functions as a neuronal receptor to recognize and select distinct pathways and synaptic targets. To test this model, we have recently generated a mouse mutant with disrupted contactin gene function. The knock-out mice display a severe neurological defect that is apparent from postnatal day 10 onwards and is characterized by ataxia, the failure to control voluntary movements, posture, and balance. The mutation is lethal by postnatal day 17. Consistent with our hypothesis, analysis of the knock-out mice revealed abnormalities in neuronal projections. Specifically, cerebellar interneurons, the granule and Golgi cells, depended on contactin for proper axon organization and elaboration of dendritic arbors. The abnormalities of cerebellar microorganization in the contactin null mutant mice are summarized in the Figure. We speculate that one consequence of these disruptions is an alteration or reduction of synapses,which in turn compromises cerebellar function and thus contributes to the ataxic phenotype of the null mutants. Using the contactin mutant mice, we now testing this model. We are also investigating the ligand interactions of contactin in the cerebellum. In vitro, contactin binds to multiple ligands of the immunoglobulin and tenascin families, as well as to receptor tyrosine phosphatase beta and contactin-associated protein (Caspr). Intracellularly, contactin is associated with a signal transduction pathway that involves the src-related tyrosine kinase fyn. To further understand contactin-induced signaling, we seek to identify the components of signal transduction pathways activated by engagement of contactin with specific extracellular ligands.

Another interest in our laboratory is understanding the function of T-cadherin (T = truncated), a GPI-linked cadherin cell adhesion/recognition molecule that mediates calcium-dependent, homophilic cell adhesion. We have recently discovered the specific localization ofT-cadherin in area CA3 and the dentate gyrus of the mouse hippocampus. This restricted expression in areas of synaptic contact leads us to hypothesize that T-cadherin plays a role at synapses. T-cadherin could serve either as a receptor on neurons to recognize synaptic targets, or as a modulator of adhesive interactions that control synapse positioning and efficacy. To test this prediction, we have generated mice with disrupted T-cadherin gene function. The null mutants appear phenotypically normal suggesting that T-cadherin is not required for vital functions. The mutant mice are currently being used to investigate the requirement of T-cadherin in hippocampal development and function.

We are also interested in the molecular mechanism of T-cadherin-mediated cell signaling and cytoskeletal rearrangement in the growth cone. In vitro experiments with chick peripheral neurons have shown that T-cadherin-mediated interactions cause local collapse of growth cone filopodia, followed by recovery of axon growth into a new direction. To understand how activation of T-cadherin causes cytoskeletal rearrangements in the growth cone, we are using biochemistry and in vitro assays to identify and test for molecules associated with T-cadherin and involved in T-cadherin-activated signal transduction.

Cerebellar Microorganization Cerebellar Interneurons
Contactin is Necessary for Cerebellar Microorganization Cerebellar interneurons, the granule and Golgi cells, display abnormal organization in contactin mutant mice. In the figure, the morphologies of these neurons are compared in the wild-type and contactin null mutant cerebellum. Granule cells require contactin for the orientation and efficiency of parallel fiber fasciculation, and the extension of distal dendritic branches. Golgi cells also depend on contactin for dendrite extension, and may need contactin for synaptic interactions with granule cells.

About Barbara Ranscht

Experience

Barbara Ranscht earned her Ph.D. in Cell Biology/Developmental Neurobiology from the University of Tübingen, Germany in 1981. Her postdoctoral training was at King's College in London, UK, and the Massachusetts Institute of Technology in Cambrigde, MA. Dr. Ranscht joined Sanford-Burnham in 1987, and holds an adjunct professorship in the Department of Neurosciences at University of California, San Diego. From 1989 to 1992, Dr. Ranscht was the recipient of a McKnight scholarship.

Education

Ph.D., University of Tübingen, Germany Neurobiology, 1981

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