Abstract
The intricate organization of the neurons and synapses that make up the human nervoussystem is fundamental to our ability to interact with the world around us. The proper function of these
networks relies heavily on the proper organization of neurons and their processes during
development. Disruptions to this process can result in developmental and degenerative pathologies,
including autism spectrum disorders, Down Syndrome, and blindness. Successful neural organization
relies on interactions between molecules that couple neurons to their appropriate partners, followed
by synaptic activity to solidify the neural connections between those partners. Here, we focus on a
cell adhesion molecule family, the Down Syndrome Cell Adhesion Molecules (Dscams), and their
roles in signaling and how these processes contribute to neural development, and their loss to
degeneration through several studies.
In the first study, we demonstrate that retinal neurons maintain a level of plasticity after
maturity that allows modification of their receptive fields and synapses based on cellular density. In
the second study, we test the requirement of Dscaml1 in the formation and maintenance of the rod-to-
rod bipolar cell synapses during aging. We show that the rod-to-rod bipolar cell synapse is properly
formed and maintained through aging even in the absence of Dscaml1. However, the number of
neurite invaginations in rod spherules increases even though the number of dendritic tips on rod
bipolar cells is reduced. We also demonstrate that loss of Dscaml1 results in smaller, and less
complex, mitochondria that may provide insight into the possibility that intracellular changes may
contribute to diseases linked to mutations in Dscaml1, including congenital stationary night
blindness. In the third study, we use a unique Dscaml1 loss of function model to map the expression
of Dscaml1 in the mouse brain that adds versatility when compared to antibody and in situ labeling
which are limited by availability and nuclear labeling. While incorporating undergraduate education,
we generated a reference tool that shows Dscaml1 expression in both cell bodies and axon tracts.
Finally, we tested possible downstream interactions of DSCAM by utilizing loss and gain of function
mouse models to measure genetic interactions between Dscam and Dyrk1a. We provide evidence that
Dyrk1a acts downstream of Dscam in several aspects of neural development including developmental
cell death and neurite lamination, and that DSCAM regulates DYRK1A location and concentration
within the mouse brain.
These works contribute to understanding how Dscams regulate and contribute to neural
development and degeneration, provide insight into the underlying mechanisms of how a single cell
adhesion molecule can regulate multiple processes throughout development, and set the groundwork
in targeting cell adhesions molecules as novel therapeutic targets in many neural pathologies.