Molecular Mechanisms of Subcellular Development: Down Syndrome-Related Genetic Interactions and Axon-Dendrite Coordination During Neurodevelopment

Abstract

Mechanisms of dendrite and axon patterning are important in both neurotypical development and neurodevelopmental disorders. This dissertation aimed to address two open questions concerning mechanisms of subcellular development: (1) How do multiple upregulated genes in Down syndrome (DS) models interact to cause aberrant axon morphology; (2) In response to changes in circuitry, how does the Wnd/DLK pathway coordinate dendritic signaling with changes at the axon terminal? Both projects employed Drosophila genetics, confocal microscopy, and biochemical techniques to interrogate these uncertain molecular mechanisms. Moreover, to test for changes in axon and dendrite morphology, these works utilized larval Class IV dendritic arborization (C4da) neurons. In the first half of this dissertation, I will describe how multiple DS-related genes interact to establish axon morphology. We found that Amyloid precursor protein-like (Appl) upregulates Down syndrome cell adhesion molecule (Dscam) to promote axon terminal growth in C4da neurons. Furthermore, we found that the post-transcriptional regulation of Dscam by Appl may occur through altered Rab5 signaling. This shows a novel, developmental mechanism of two DS-related genes interacting to establish aberrant axon morphology. The second half of this dissertation interrogates the coordination of axon-localized events to dendritic signaling. We found that ablation of second order neurons (SONs) within the C4da nociceptive pathway resulted in decreased expression of nuclear Knot, a dendritic growth regulator. This phenocopies activation of the Wnd/DLK pathway. Moreover, Wnd/DLK required retrograde transport to repress nuclear Knot expression. This lays the foundation for determining how the Wnd/DLK pathway may coordinate axonal events to dendritic growth to maintain functional circuitry in response to changes at the axon terminal. Overall, this work offers insight into basic and DS-relevant mechanisms of axon-dendrite patterning in development. Future works may further these findings in mammals and consider the implications of DS-gene interactions as well as the impact of axonal changes on dendritic structures for therapeutic interventions in neurodevelopmental disorders.