HOW IS GENE EXPRESSION CONTROLLED ACROSS SPACE AND TIME TO ENSURE PROPER CIRCUIT FORMATION?
Wiring a complex brain requires genes to switch on at the right time and in the right place. When this timing or location goes wrong, as often happens in neurodevelopmental disorders, normal wiring is disrupted. Using the fruit fly and the mouse as model systems, we aim to understand: 1) How does the developing brain control where and when genes are expressed? 2) How are these mechanisms disrupted in neurodevelopmental disorders like autism and schizophrenia?
Key Findings
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).
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We found that upper layer excitatory neurons in the mouse cortex form a continuum of cell-identities rather than discrete cell-types. Cell identities continuously vary with cortical depth. The development of this continuum is controlled by genetically hardwired and experience-dependent mechanisms.
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 are spatial gradients and timing controlled in the mammalian cortex?
We apply single-cell and spatial genomics in the mouse cortex to understand spatial continua of cell identities and timing of gene expression are controlled. We are particularly interested in the role of regulators of gene expression disrupted in psychiatric disorders such as autism and schizophrenia.
