Neurons adopt proper morphologies to form functional neuronal circuits. Although the three basic morphologies?multipolar, bipolar and unipolar?are universally conserved across animal species, little is known about how they are determined. Recent studies by our laboratory have demonstrated that the transcription factor Dendritic arbor reduction 1 (Dar1) is necessary and sufficient for the multipolar morphology of neurons in Drosophila. Dar1 is exclusively expressed in multipolar, but not bipolar or unipolar, neurons, regardless of the cell lineages that the neurons are derived from. Loss of dar1 converts multipolar neurons into bipolar or unipolar morphologies without affecting their molecular identities or axon development. These lines of evidence suggest that neurons from different lineages activate the same terminal differentiation program to assume one of the three basic morphological types. However, it remains unknown how this common genetic program for morphology is activated in neurons from diverse lineages. Here, I propose to address the mechanistic link between neuronal fate specification and the shared program that determines the basic morphological types. I will investigate the genetic program that determines the basic morphological types by identifying the mechanism that controls Dar1 expression. I have found a fragment in the dar1 locus that is sufficient to recapitulate the endogenous Dar1 expression pattern, suggesting this fragment contains essential cis-regulatory elements of Dar1. In the Specific Aim 1, I will identify the minimal enhancer element(s) that specifies Dar1 expression in multipolar neurons in vivo and characterize the activity of this minimal enhancer in multipolar neurons within SOP lineages by using a novel and improved Brainbow system that we have developed. In the Specific Aim 2, I will identify the transcriptional regulators that determine Dar1 expression in multipolar neurons. I will test whether Dar1 expression is regulated by lineage-specific proneural regulators and a co-factor shared by different neuronal lineages. Successful completion of this study will address the gap in knowledge of how different types of neurons genetically regulate a terminal selector, Dar1, to determine the basic layout of neuronal morphology. It will also provide insights for future studies that aim to guide neuronal regeneration in injured nervous system.
Neurons differentiate to gain morphological properties; however, how different types of neurons gain a common morphological property remains unknown. Using Drosophila melanogaster as a model organism, I propose to address this gap in knowledge by studying the molecular programs through which fate-specified neurons acquire a specific morphological feature. The proposed research seeks the fundamental knowledge about nervous system development, and has the potential to reduce the burden of neurological disease by providing the basic research needed to develop therapies to regenerate damaged neurons that can properly integrate into existing neuronal circuitry.