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Associate Professor of BiologyAssociate Professor of
Office: 355 BBIowa City, IA 52242
Email: firstname.lastname@example.orgWeb: More About Dr. Weiner - Related Websites and Resources
BA, Psychology, Northwestern UniversityPhD, Neurosciences, University of California-San Diego
Post Doctorate, Anatomy and Neurobiology, Washington University School of Medicine
Interdisciplinary Graduate Program in GeneticsInterdisciplinary Graduate Program in NeuroscienceInterdisciplinary Graduate Program in Translational BiomedicineMedical Scientist Training Program
A defining attribute of the vertebrate nervous system is the remarkable specificity with which different neuronal subtypes interact during development. Specific cell-cell interactions are critical for setting up the correct patterns of histogenesis, neuronal survival, axon outgrowth, and synapse formation. Research in our laboratory is focused on understanding the roles that adhesion molecules, which protrude from the cell membrane to link adjacent cells together, play in these processes.
Three large clusters of cadherin-related genes (Protocadherin-a, -ß, and -?) lie in a tandem array on a single chromosome in mammals. The ? cluster, on which we focus, consists of 22 ""variable"" exons, each of which encodes the extracellular, transmembrane, and partial cytoplasmic domains of a single protocadherin isoform. Each variable exon is spliced to a set of three ""constant"" exons which encode a shared C-terminal domain. Thus, a variety of adhesive specificities may link into a common signaling pathway.
Our work has shown that ?-protocadherins are expressed exclusively in the nervous system during development, and are concentrated at synapses. Mice in which the entire ?-protocadherin locus is deleted lack voluntary movements and reflexes and die at birth due to massive apoptosis of spinal interneurons and loss of synapses. We have recently genetically dissociated these two phenotypes to show that control of synapse development is a primary function of ?-protocadherins.
We are currently addressing several questions using multiple lines of mutant and transgenic mice: 1) What is the relationship between the observed synaptic defects and apoptosis?; 2) How are ?-protocadherins localized to synapses and what signaling pathways do they require?; 3) Why are only certain interneurons affected, since most neurons express ?-protocadherins? We hope to use insights gained from studying the phenotype of protocadherin mutant mice to elucidate general mechanisms of neuronal survival and synaptic specificity.
The immunoglobulin superfamily molecule ALCAM is expressed by subsets of neurons and has been implicated in the control of numerous developmental and pathological processes. To test hypotheses about ALCAM function, we have disrupted its gene via homologous recombination. In mice lacking ALCAM, both motor neuron and retinal ganglion cell axons fasciculate poorly and are occasionally misdirected. In addition, ALCAM mutant retinae exhibit dysplasias with photoreceptor ectopias that resemble the retinal folds observed in some human retinopathies. This appears to be due to loss of ALCAM in the choroid, a pigmented vascular tissue that lies behind the neural retina. Because ALCAM has been associated with melanoma metastasis, we hypothesize that defects in choroidal melanocyte adhesion and/or motility underlie the mutant phenotypes. We now are determining the specific cellular defect and examining its relationship to ocular development and disease processes.
Date Last Modified: 06/06/2016 -
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