Welcome to the David Chen’s Lab!
Are you curious about how the brain wires itself during development? Are you fascinated by how sensory information like sight and taste gets translated into brain activity? In our lab, we study how immature neurons acquire specific molecular and morphological features and form precise connections during development to create functional circuits that allow organisms to sense and respond to the world.
We use the fruit fly, Drosophila, as our primary model organism. Why? Because its simple nervous system allows us to investigate how specific genes and molecules guide neurons to find their correct partners. We use a variety of cutting-edge techniques, including single-cell genomic technologies, cell-type-specific genetic manipulations, and high-quality brain EM connectomes, to probe the organizational principles of building two distinct sensory circuits during development: the Drosophila visual and gustatory systems.
Overview
During neuronal development, sensory neurons are specified into correct cell fates and connect to proper partners. The formation of functional circuits is essential for animals to detect environmental inputs and thus drive behaviors. Dissecting the molecular logic for establishing sensory circuits in higher-order organisms has been challenging, partly due to the complexity and diversity of their nervous systems. For example, there are 86 billion neurons in the human brain: ten times the current global population. If forming the correct neuronal connection is like shaking hands with the right partner, how many attempts would be needed during development to establish the sensory circuits that process our sensory cues? In addition, before neurons connect to the correct partners, how are they specified, and how do they acquire their distinct morphological and molecular features (e.g., develop specific neuronal morphologies and the expression of sensory receptors and neurotransmission machinery)?
While Drosophila has been a powerhouse model system for studying the fundamental principles of neuronal development and function, progress at the neuron and circuit-specific levels during development has been limited by the lack of tools to manipulate developmental neurons. We have recently developed a method to target specific neurons from early development to adulthood (Chen et al., 2023 PNAS). This toolkit provides a unique approach to uncover how neurons establish and maintain precise connectivity.
Current Projects (primary on the Drosophila visual system)
Uncovering the Molecular Controls of Neuropil Targeting in Developing Sensory Circuits
How do developing neurons know where to extend their branches in the brain? Understanding how immature neurons develop specific structures that allow them to connect with precise brain regions is a key question in our lab. We are using the TmY14 neuron in the Drosophila visual system to tackle this challenge. TmY14 neurons extend branches to multiple regions — the medulla, lobula, lobula plate, and the central brain. We have identified three transcription factors that specifically regulate projections to the lobula. Our ongoing work focuses on unraveling the molecular network involving these transcription factors and identifying the downstream signals that direct neuronal targeting and circuit formation.
Maintaining the Retinotopic Map: Decoding Precision in Visual Circuit Wiring
Imagine a perfectly aligned grid, where each point in the eye corresponds exactly to a point in the brain. This precise organization, called retinotopy, is essential for maintaining spatial accuracy in visual processing. But how are these connections established during development?
Our lab investigates this question using the Y3 neuron in the Drosophila visual system. During early pupation, Y3 neurons send projections to the lobula and lobula plate but only extend their branches to the medulla later in development. This delayed targeting suggests that more than just birth order governs connection specificity.
We aim to identify candidate molecular regulators using Y3 developmental transcriptomes and to test how these molecules influence Y3 neurite targeting in the medulla. Additionally, we will assess whether other cell types, such as T4/T5 neurons, act as “guiding wires” by selectively ablating them and observing the impact on Y3 neuron targeting. Our goal is to reveal how a precisely organized grid of cells is constructed during development, ensuring that visual information is accurately mapped from the retina to the brain.
Identifying Molecular Controls of Stochastic Color Vision Circuit Assembly
Previous work in my postdoc lab (Claude Desplan’s lab) demonstrated that stochastic color photoreceptors (yR7) connect to deterministic partners in the medulla (yDm8) through two immunoglobulin superfamily (IgSF) proteins (Dpr11-DIPγ). During my postdoc, I identified another IgSF pair from the Beat and Side family, guiding the pale counterparts (pR7 to pDm8). This y/p information needs to be propagated throughout the circuit.
The main outputs of Dm8 are projection neurons that connect to the lobula in the optic lobe. It is unclear how the y/p organization of the eye (R7/R8) and medulla (y/pDm8) is preserved in the lobula neuropil or the central brain. We will use published EM connectome data to identify the targets of y/p-specific projection neurons and examine the y/p columnar organization in the lobula. We will also prevent the generation of y or pR7s (using Ss gain- or loss-of-function) and generate scRNAseq libraries to determine which neural types depend on the presence of y/p neurons. Our work aims to uncover how stochastic decisions propagate to downstream partners at the system level.
Building Tools to Decode Brain Wiring
Expanding the Genetic Toolkit to Decode Brain Wiring
How do we identify and manipulate specific cell types in the brain to study their function? Our lab addresses this challenge by creating precise genetic tools that allow us to target specific neuron types across all developmental stages in Drosophila.
Our approach leverages single-cell RNA sequencing (scRNAseq) data to develop gene-specific split-GAL4 lines. Unlike existing enhancer-based genetic tools that often lack specificity and may not work consistently throughout development, our method focuses on regulatory elements identified through scRNAseq. This results in highly predictive, reliable tools for targeted genetic manipulation.
During my postdoc, I led a team of undergraduates to streamline the protocol for generating split-GAL4 lines (Li & Li et al., 2023 Star Protocol). Using this protocol, approximately 3,000 fly lines from the Drosophila Stock Center can be converted into split-GAL4 lines, facilitating precise targeting of cell types across various tissues. Our lab actively collaborates with researchers at Columbia, UPenn, and the University of Toulouse to expand the toolkit and apply it to diverse developmental and functional studies in Drosophila neurobiology.
Why Join Us?
Are you someone who loves to ask questions, solve puzzles, and learn new techniques? Whether you’re interested in genetics, neurobiology, or computational analysis, our lab offers a welcoming and supportive environment where you can develop your skills while contributing to groundbreaking research. We’re actively recruiting undergraduates, graduate students, and postdocs who are passionate about understanding how the brain builds itself, one neuron at a time.
Ready to learn more? Reach out to us to discuss research opportunities and find out how you can be part of the team!