Projects

g-Pcdhs

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Neurons use two different strategies to promote self-avoidance, the process that prevents sister neurites from the same cell ("self") or same cell type ("homotypic") from entangling with each other. The first relies on molecular diversity to provide each neuron with a unique “barcode”, allowing it to distinguish “self” from “non-self”. In mammals, this is typified by the clustered protocadherins (Pcdhs), members of the cadherin superfamily of cell adhesion molecules (CAMs). We focus on the gamma cluster, which is composed of 22 different isoforms, and is required for normal self-avoidance in starburst amacrine cells in the mouse retina. We use combinations of gene editing and gene delivery techniques to ask questions about isoform diversity and specific isoform functions.

"self"

Isoform matching = repulsion

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"non-self"

Isoform mismatch = overlap

Dscams

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The second strategy neurons use for self-avoidance does not depend on molecular diversity. The Dscams (DSCAM, for Down syndrome cell adhesion molecule, and the similar DSCAML1) are members of the Ig superfamily of CAMs required for self-avoidance and homotypic avoidance. Dscams in mammals are not diverse, but functionally interact with other CAM systems to mask excessive adhesion allowing neurites to be indifferent to each other. When left unopposed in Dscam mutants, unmasked adhesion pulls neurites into fascicles and cell bodies into homotypic clusters. We use in vivo and in vitro techniques to investigate mechanisms of adhesive masking, and how they differ between cell types.

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Dscam+/+

Dscam-/-

Dopaminergic amacrine cells

Manipulating the complement of cell adhesion molecules expressed in neurons changes their propensity to fasciculate with each other, supporting the model that DSCAM "masks" other CAMs. From Garrett et al., PNAS, 2018

In mice null for Dscam, many neuronal subtypes in the retina, including dopaminergic amacrine cells, form homotypic clusters and fascicles. Images from Garrett et al., eLife, 2016