The number of neurons in our brains is vast, and the connections among them of an even greater magnitude. The Clowney lab asks how the information to construct the brain is encoded in the genome. How does development efficiently make use of finite genomic information to build the brain? How are genes and gene regulatory modules organized along the chromosome? How have these patterns evolved? To answer these questions, we focus on chemosensory systems, where signals from the environment are distributed across large families of receptor molecules and interpreted by higher-order neurons through combinatorial coding.
Project 1: The patterning of sex-specific circuits for sexually dimorphic mating behaviors
In previous work, we identified a neural circuit that allows male fruit flies to identify other individuals as “good mates” and initiate courtship displays. This circuit forms only in males, due to the action of a male-specific transcription factor, called Fruitless. Now, we are asking how Fruitless acts on the genome to masculinize this circuit, altering the number of cells of particular classes, their anatomy, connectivity, and adult physiology. We are using a combination of molecular dissection techniques, including ATAC-seq; imaging; genetics; and circuit mapping to determine “How flies swipe right.”
Project 2: Non-deterministic wiring in the mushroom body.
Most of the objects we encounter on a day-to-day basis were not present during evolution. How does the brain represent these evolutionarily unpredicted objects? The majority of neurons in the human brain are likely to receive combinatorial sensory input to allow us to perceive arbitrary objects as combinations of sensory features. Non-deterministic patterning of the inputs to these neurons would be a genetically efficient way to maximize the objects that can be perceived and discriminated from one another without inscribing meanings to them a priori. In this project, we are studying the development of olfactory inputs to the fruit fly associative learning center, the mushroom body. Individual Kenyon cells of the mushroom body receive discrete and unpredictable combinations of olfactory inputs, with different cells receiving different inputs and the suite of possible combinations likely different across individuals. How do Kenyon cells know how many inputs they ought to receive? How is diversity generated such that the sets of inputs to each cell is different? To answer these questions, we are using a combination of in vivo longitudinal imaging, developmental circuit perturbations, and transcriptional profiling techniques including single cell RNAseq.
Project 3: Engineering development to test form-function relationships in olfactory coding
Theoretical models can predict the potential utility of circuit motifs, but these models are generally not tested via experimental perturbation. In the mushroom body, we are developing methods to manipulate neural circuit development in order to test how changes in circuit architecture affect sensory coding. To do this, we combine genetic and chemical perturbations during development with functional imaging and behavioral analyses in the adult.
Project 4: A common genomic architecture for sensing the external world
The radiation of mammals at the extinction of the dinosaurs produced a plethora of new forms, as diverse as bats, whales, and horses, in only 10-20 million years. Less visibly, the ability of mammals to exploit a variety of niches is supported by extensive diversity in repertoires of molecules sensing and responding to the external environment, including chemosensory receptors; peptides and receptors for barrier defense; and enzymes for xenobiotic metabolism. Indeed, reports of new mammalian genomes frequently detail extensive innovation in these gene categories, including olfactory receptors (in a variety of vertebrates); natural killer cell receptors (e.g. in mouse, bat, platypus, and human); xenobiotic enzymes (e.g. Cytochrome P450 enzymes in platypus); and antimicrobial peptides (e.g. defensins in opossum).
We hypothesize that non-canonical gene regulatory mechanisms common to these niche-interaction gene families allowed their evolutionary diversification and govern their function today. In particular, we find that genes involved in interaction with the external world are partitioned into AT-rich regions of the genome, while genes involved in core cellular and developmental functions are partitioned into GC-regions of the genome. To interrogate the emergence of this pattern and its function, we are taking a computational approach, asking how “outward-looking” gene families have emerged across vertebrates, and the mechanisms by which these gene families are diversified among humans.