08 February 2024
#TechTalk: New Confocal Fluorescence Microscope at the Stowers Institute
Q&A with Tom Kleist, Ph.D, a member of the Institute’s Microscopy Technology Center
Our research integrates developmental neurobiology with systems biology and gene regulation with the goal of understanding brain wiring.
Neuroscience, Development and Regeneration, Genetics and Genomics, Molecular and Cell Biology, Systems Biology
The Özel Lab investigates how neurons differentiate into different types with distinct functions and connections during development. The lab seeks to uncover the gene regulatory mechanisms responsible for governing neuronal cell fate and circuitry.
The Özel Lab will be an interdisciplinary, international, and collaborative team of computational and experimental biologists working together with the goal of understanding brain development. The lab anticipates that insights from their research will have broad translational applications such as inducing stem cells to differentiate into specific neuronal types for cell replacement therapy.
Stowers Institute for Medical Research
Neşet Özel, Ph.D., a neuroscientist, will join the Stowers Institute in the fall of 2023 as an Assistant Investigator. Özel’s research combines genetics, imaging, single-cell genomics, and computational modeling approaches to understand the fundamental molecular mechanisms that control brain development in Drosophila.
Gaining a thorough understanding of the molecular mechanisms that underlie neuronal diversity and synaptic connectivity is our only hope to ever have effective treatments for a variety of neurodevelopmental disorders, most notably autism. However, we still lack the tools and the depth of understanding to comprehensively address these questions at the level of complexity of mammalian brains.
Thus, our research focuses on the Drosophila visual system, the premier model nervous system whose cell-type diversity and connectome has been described in great detail, providing the ideal balance between complexity and accessibility.
Combined with the powerful genetic tools we can take advantage of in flies, this allows us to answer the most fundamental questions about brain development that are too intractable in “higher” organisms.
tSNE visualization of the single-cell transcriptomes acquired from adult Drosophila optic lobes (Özel et al. 2021, Nature). Clusters annotated to specific neuronal types are represented by their standard abbreviations. Other clusters are represented by their number.
The Özel Lab will be an interdisciplinary team of computational and experimental biologists, working together with the singular goal of understanding brain development.
We are a question-driven lab that does not hesitate to explore and adopt a wide range of cutting-edge tools and methods to address the most challenging aspects of this overarching question. All our members, regardless of their background, are encouraged to train in both “wet” and “dry” lab techniques to realize their full potential.
The lab believes that an inclusive environment where ideas and concerns are shared openly is essential for the advancement of science; thus we celebrate the diversity of opinions and perspectives afforded to us by our highly international and collaborative environment.
More about the Özel Lab's research
Neuronal type identity is central to the development and function of neural circuits, as it instructs both the connectivity of neurons as well as their physiological properties. Our previous work has identified the combinations of transcription factors (terminal selectors) that encode the unique identity of ~200 distinct neurons in the Drosophila visual system. Connectivity of this circuit is genetically “hardwired” and highly stereotypical: each neuronal cell type will only form synapses with a specific subset of other neuronal types in its vicinity while avoiding others. While this implies that terminal selectors must also control connectivity along with other type-specific features of neurons, the gene regulatory mechanisms that link early cell fate decisions to neuronal differentiation and circuit formation are still mostly unknown.
Research in our lab combines high throughput single-cell analyses of gene expression and chromatin accessibility (multiomics) with advanced computational modeling approaches to generate hypotheses on transcription factor function in specific neurons. These hypotheses are then immediately addressed at the bench through state-of-the-art genetic and imaging approaches.
From specification to differentiation: Although terminal selectors control the identity of neurons, the initial specification of these fates are instructed by patterning mechanisms in neural stem cells. These are generally mediated by transiently expressed transcription factors which are often not maintained in postmitotic neurons. How the combined action of these transient mechanisms are converted into a stable selector code in newborn neurons remains unknown. By studying the differentiation trajectories in single-cell multiomics data acquired during neurogenesis, we aim to identify the cis-regulatory elements that control the initial activation of unique selector combinations in each neuron, as well as the upstream regulators that act on these elements. Our ultimate goal is to produce the first comprehensive description of a gene regulatory network that generates neuronal diversity in a complex brain. We hope that insights gained from these studies will have broad translational implications, such as targeted differentiation of induced stem cells to specific neuronal fates for cell replacement therapy.
Gene regulatory networks of synaptic specificity: We have shown that terminal selectors control all type-specific features of optic lobe neurons, including connectivity. Yet the regulatory networks that control brain wiring downstream of selectors are still mostly unexplored. Our goal is to first produce computational models of these networks using gene regulatory network (GRN) inference algorithms that can integrate genome-wide gene expression and cis-regulatory (multiome) datasets to accurately predict the target genes regulated by each transcription factor. Experimental validations of these models then allow us to describe the regulatory subroutines that control specific cellular decisions during neuronal development. We propose that this “top-down” approach to study brain wiring, i.e., first identify transcription factors that cause broad changes and then move down to the effector targets guided by computational models, can overcome the challenges more “bottom-up” approaches have been facing due to widespread redundancies among cell-surface proteins that ultimately control intercellular interactions. In the long-term, our results may enable to engineer ‘designer’ neurons that can be targeted to desired brain areas and form synapses with a predictable set of partners.