Gene-regulatory mechanisms of neuronal circuit formation in Drosophila

/Abstract Brain function depends on the precise assembly of neural circuits during development, but the gene-regulatory principles that govern how neuronal lineages integrate into functional circuits remain poorly understood. Using the Drosophila Ventral Nerve Cord (VNC) as a model, this project investigates how specific neuronal lineages assemble into circuits, focusing on the Jump Circuit—a key and conserved pathway for escape behavior. Aim 1 (K99) will explore how neuronal identity influences connectivity within the jump circuit. I hypothesize that segment-specific morphologies, regulated by neuronal identity, enable interactions between interneurons and the motor neuron controlling the jump response. I will employ genetic manipulation, expansion microscopy, and single-cell RNAseq data to link neuronal identities to their transcriptomes and connectivity patterns, ultimately determining if segmental identity genes regulate motor neuron connectivity. My collaborators Drs. Jefferis and Tillberg will help me develop the technical expertise to complete this aim. Aim 2 (K99) seeks to map the composition and function of the jump circuit. In collaboration with Dr. Azevedo, I will generate a complete synapse-resolution map of the jump circuit and analyze the role of neuronal activity in circuit formation and function. This aim will reveal whether early neurotransmission is crucial for proper circuit assembly and maturation. Aim 3 (R00) will investigate how epigenetic factors regulate neuronal identity during circuit formation. Drawing on insights from Aims 1 and 2, I will examine how epigenetic mechanisms control neuronal behavior during circuit assembly. Career Development Plan and Goals: To achieve my goal of becoming an independent scientist, I will execute this research mentored by Dr. Lacin, at the University of Missouri – Kansas City (UMKC), who is a leading expert in the field of neuronal development in the VNC. Furthermore, I have assembled a dedicated mentoring team, including Dr. Spletter as co- mentor. Dr. Lacin's expertise in developmental neurobiology, Dr. Tillberg's expertise in expansion microscopy, Dr. Jefferis' expertise with generating and analyzing single-cell RNAseq data, and Dr. Azevedo's focus on mapping neural circuits will provide a robust foundation for my research. With support from these experts, I will develop a deep understanding of neural circuit formation, microscopy techniques, and gene-regulatory mechanisms governing neural connectivity. The environment at UMKC, enriched by these collaborations, will enable me to transition to an independent research program. Project Number: 1K99NS146609-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Neurological Disorders and Stroke (NINDS) | Principal Investigator: Jelly Soffers | Institution: UNIVERSITY OF MISSOURI KANSAS CITY, KANSAS CITY, MO | Award Amount: $137,687 | Activity Code: K99 | Study Section: Special Emphasis Panel[ZRG1 CN-J (90)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11283828