HOW IS GENE EXPRESSION CONTROLLED ACROSS SPACE AND TIME TO ENSURE PROPER CIRCUIT FORMATION?
Hormone-induced TFs show similar dynamics in all neuron-types. Their targets are neuron-type specific
Proper wiring of animal brains heavily relies upon proper timing and this includes expressing the right sets of genes at the right time. Particularly, during synapse formation, gene expression is highly dynamic and cell-type specific. In fact, the same gene can have highly divergent expression dynamics across different cell-types. As neurons do not develop in isolation, but rather depend upon specific, timely interactions with other cell-types, it is also evident that there would need to be some level of coordination amongst the different neuron-type specific dynamic genetic programs.
Thus, a key question is: how are the timing, coordination and specificity of complex gene expression programs controlled in developing nervous systems?
We discovered an elegant solution to this problem in the fly visual system. We found that timing is determined by a cascade of transcription factors initiated by the steroid hormone, Ecdysone. These transcription factors are expressed with the same dynamics across cell-types, but the genomic targets of these TFs are highly cell-type specific. Cell-type specificity comes from the activity of cell-type specific TFs (also called selector TFs).
The specific questions we are now pursuing are:
What role does timing play in wiring the brain? How is timing controlled at a molecular level?
We use genetics, genomics and molecular biology approaches in fly visual system neurons to identify mechanisms that allow temporal regulators (such as signaling pathways) and cell-type specific TFs to combinatorially control gene expression, and then investigate how dynamics of their target genes contribute to wiring specificity
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How is timing controlled in the mammalian cortex?
We use single-cell RNA-seq and ATAC-seq in neurons in the mouse visual cortex to understand the temporal and cell-type specific regulation of gene expression programs during key phases of circuit formation. We are particularly interested in the role of signaling pathways in determining proper timing and how this regulation is disrupted in psychiatric disorders such as autism and schizophrenia.