Understanding the regulation of neuron cell number and arbor size

About This Grant

How sensory neurons scale their dendrites to evenly sample their environment is an unanswered question in biology. The Drosophila visual system presents an ideal model to answer this question. The fly visual system is hard-wired and iteratively organized, such that 800 repeating unit eyes project their arbors to an equal number of repeating columns in each downstream processing center. In one such processing center, the medulla, twenty types of Distal medulla (Dm) neurons evenly scale their arbors to regulate the flow of visual information down the optic lobe. As these neurons integrate information from between multiple photoreceptor columns, these cells must tightly regulate their number, shape, size and spacing. Drosophila Dm neurons exhibit 5 to 750 neurons per cell type, and each neuron class possesses a distinct morphology/arbor size. Recently, my postdoctoral lab obtained multiple single-cell RNA sequencing (scRNAseq) datasets that allowed us to identify patterns of gene expression specific to each cell type, as well as the dynamics of how gene expression changes within each cell during important developmental stages such as neurite targeting and synaptogenesis, providing us with an ideal tool to identify candidate regulators of neurite targeting in the optic lobe. During my postdoc, I completed the first aim of my K99 under the mentorship of Claude Desplan at New York University. There, I determined that Dm neurons were born from a neuroepithelial crescent that is spatially subdivided into differently sized domains based on the expression of distinct transcription factors; this patterning allows for the generation of distinctly sized stem cell pools, each of which generates neurons in specific proportions. This spatial patterning is not sufficient to generate all neural diversity, and I discovered that a second pathway involving the conserved morphogen Dpp/BMP divides each domain into smaller pools to generate the rarest cell types. This work was published on the cover of Developmental Cell. Now, as an independent investigator at City College (CUNY), I will complete the second aim of my project, which will be funded by my R00 award. During this period, I will determine the genetic processes that dictate the size and orientation of Dm neuron arbors. Preliminary data have identified potential candidate regulators, including a highly conserved transcription factor important in somatosensory neuron targeting, a neuropeptide, and the vesicular glutamate transporter. I will combine my genetics experimentswith live imaging to quantitatively characterize how multicolumnar neurons determine the orientation and size of their arbors, as well as how these processes go awry in mutants. My work will determine how low-abundance neurons scale their arbor size to ensure uniform sampling of their environment, a problem common to many brain regions in most species