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BARBARA RANSCHT, PH.D.
Professor
Tumor Microenvironment
858.646.3122 (phone)
858.646.3197 (fax)
ranscht@burnham.org
RESEARCH FOCUS, BIOGRAPHY, STAFF, PUBLICATIONS
Research Focus
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.
Biography
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 The
Burnham Institute 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.
Selected Publications
Berglund, E.O., Murai, K.K., Fredette, B., Sekerkova, G., Marturano, B., Weber, L., Mugnaini, E., and Ranscht, B. Ataxia and Abnormal Cerebellar Microorganization in Mice with Ablated Contactin Gene Expression. Neuron 24:739-750, 1999.
Boyle, M.E.T., Berglund, E.O., Murai, K.M., Weber.,L, Peles, E., and Ranscht, B. Contactin orchestrates assembly of septate-like junctions at the paranode in myelinated peripheral nerve. Neuron 30,
385-397, 2001.
Murai, K.M., Misner, D., and Ranscht, B. Contactin supports synaptic plasticity associated with hippocampal long-term depression, but not potentiation. Current Biology 12:181-190, 2002.
List of Publications via PubMed
(NIH National Library of Medicine)
RESEARCH REPORT
ESTABLISHMENT OF AXON PATTERNS IN DEVELOPING EMBRYOS
(Download report as PDF)
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.
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.
