Date of Degree

9-2022

Document Type

Dissertation

Degree Name

Ph.D.

Program

Biology

Advisor

Greg R. Phillips

Committee Members

Dan McCloskey

Leora Yetnikoff

Paul Forlano

Reed Carroll

Subject Categories

Biology | Cell and Developmental Biology | Neuroscience and Neurobiology

Keywords

Gamma Protocadherins, neurodevelopment, cell adhesion, synaptogenesis, self-avoidance

Abstract

Clustered protocadherins (Pcdhs) constitute a family of cell adhesion molecules with approximately 60 Pcdh genes clustered in a 1 MB locus on chromosome 5q31 in humans. The Pcdh gene cluster is subdivided into α, β, and γ subclusters which encode related proteins. Individual neurons activate different subsets of Pcdh-α, Pcdh-β and Pcdh-γ genes by epigenetic mechanisms to generate distinct Pcdh adhesive units expressed by each neuron. This is thought to serve as a “surface barcode” for single-cell identity and synaptic recognition in the nervous system. The actual role for Pcdhs in neural development is still relatively unknown and different roles have been proposed. Late in development Pcdhs are found at synapses and have been postulated to play a role in establishment of synaptic connectivity. Early in development Pcdhs can affect the outgrowth and patterning of dendrites. In some cases, this seems to be mediated by interaction of Pcdhs between dendrites and glial cells that may stabilize these contacts. In other cases, interaction of same-cell dendrites through Pcdhs causes what is known as “self-avoidance” in which crossing is prevented by same-cell dendrites allowing for optimal expansion of dendrites into territories. Self-avoidance has also be observed in other systems and is similarly mediated by adhesion molecules. One question about self-avoidance that has yet to be answered is: How can cell adhesion molecules that presumably bind membranes together, actually cause the repulsion of these membranes. Based on previous studies, it is becoming increasingly clear that Pcdh intracellular trafficking could play an important role in synaptogenesis and dendrite outgrowth at specific times in development. A cell biological model for Pcdh function has been proposed that predicts that endocytosis of Pcdhs is a critical switch that converts Pcdhs from adhesive to avoidance molecules. To address the dual roles for Pcdhs in neural development, I have studied their association with synaptic maturation and have found that Pcdhs are positively associated with the maturation of CNS synapses in the hippocampus. This is consistent with an adhesive role at the synapse. To study a possible mechanism for self-avoidance, I identified proteins in Pcdh-γ complexes and found a novel endocytic regulator, the F-BAR protein FCHSD2. I found that Pcdh-γ’s and FCHSD2 form a complex in heterologous cells together with known FCHSD2 interacting proteins. The FCHSD2 complex has been shown to regulate the actin cytoskeleton in endocytosis. I found that this complex likely mediates endocytosis of Pcdh-γ’s but may also play a role in Pcdh-γ trafficking from the late endosome. Taken together my results reveal new insights into the function of Pcdhs at the synapse and in adhesion mediated by intracellular trafficking.

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