Joshua Weiner, Ph.D.

Joshua Weiner, PhD
Associate Professor
Biology
Research focus: 

Molecular Control of Synapse Formation and Synaptic Specificity

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A defining attribute of the vertebrate nervous system is the remarkable specificity with which different neuronal subsets 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.

Protocadherins

Three large clusters of cadherin-related genes (Protocadherin-α, -β, and -γ) lie in a tandem array on a single chromosome in mammals. The γ 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 γ-protocadherins are expressed in the nervous system during development, and are found at a subset of synapses. Mice in which the entire γ-protocadherin locus is deleted lack voluntary movements and reflexes and die at birth due to massive apoptosis of spinal interneurons and concomitant loss of synapses (Figure 2). We have genetically dissociated these two phenotypes, using mice in which apoptosis is blocked, to show that control of synapse development is a primary function of γ-protocadherins. Our work indicates that when mice lack the γ-protocadherins, synaptic density and activity is reduced, and this leads to an exacerbation of an underlying pattern of developmental cell death amongst molecularly distinct spinal interneuron populations.

We are currently addressing several questions using multiple lines of mutant, conditional mutant, and transgenic mice:

  1. How are γ-protocadherins localized to synapses and other cellular compartments, and what are the signaling pathways in which they participate?
  2. What roles to the γ-protocadherins play in synapse formation in the brain, which matures only after birth, when the constitutive mutants die?
  3. What is the function of the γ-protocadherins in astrocytes, glial cells that express multiple members of the family?
  4. Do the γ-protocadherins act exclusively or primarily as homophilic adhesion molecules, or do they engage in heterophilic interactions and/or act as signaling molecules?
  5. Does the diversity of the γ-protocadherin family provide a molecular code that underlies the specificity of synaptic interactions?

To answer these questions, we are utilizing new conditional mutant mice and several transgenic lines expressing the Cre recombinase to disrupt γ-protocadherin function in specific cell types at discrete developmental stages. We are also employing a variety of biochemical techniques to characterize the molecular interactions of the γ-protocadherins in neurons and in other cell types.

We hope to use insights gained from studying the functions of the γ-protocadherins to improve our general understanding of the ways in which synapse formation and function might go awry in a number of developmental disorders such as autism and mental retardation.

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