Abstract
The Sonic hedgehog (Shh) signaling pathway is crucial for pattern formation in early central nervous system development. By systematically analyzing high-throughput in situ hybridization data of E11.5 mouse brain, we found that Shh and its receptor Ptch1 define two adjacent mutually exclusive gene expression domains: Shh+Ptch1− and Shh−Ptch1+. These two domains are associated respectively with Foxa2 and Gata3, two transcription factors that play key roles in specifying them. Gata3 ChIP-seq experiments and RNA-seq assays on Gata3-knockdown cells revealed that Gata3 up-regulates the genes that are enriched in the Shh−Ptch1+ domain. Important Gata3 targets include Slit2 and Slit3, which are involved in the process of axon guidance, as well as Slc18a1, Th and Qdpr, which are associated with neurotransmitter synthesis and release. By contrast, Foxa2 both up-regulates the genes expressed in the Shh+Ptch1− domain and down-regulates the genes characteristic of the Shh−Ptch1+ domain. From these and other data, we were able to reconstruct a gene regulatory network governing both domains. Our work provides the first genome-wide characterization of the gene regulatory network involved in the Shh pathway that underlies pattern formation in the early mouse brain.
Highlights
Pattern formation in early animal development is controlled by signal transduction cascades, in which transcription factors (TFs) play crucially important roles as downstream effectors
We have developed a computational approach that combines publicly available high-throughput in situ hybridization (ISH) data with our own experimental data to investigate gene regulation, involving signal molecules and transcription factors (TFs), during early brain development
The analysis indicates that two key TFs, Foxa2 and Gata3, play antagonizing roles in the formation of two mutually exclusive domains established by the Sonic hedgehog signaling pathway in the developing mouse brain
Summary
Pattern formation in early animal development is controlled by signal transduction cascades, in which transcription factors (TFs) play crucially important roles as downstream effectors. The Shh signaling pathway is itself activated when Shh binds to its receptor Ptch, which, without the ligand, inhibits the cell membrane protein Smo. Shh binding removes the inhibition on Smo and triggers the activation of three GLI family TFs, Gli, Gli and Gli, which further activate or inhibit specific TFs to determine regional cell fate. Shh binding removes the inhibition on Smo and triggers the activation of three GLI family TFs, Gli, Gli and Gli, which further activate or inhibit specific TFs to determine regional cell fate Identifying those downstream TFs and how they work is a central task in the elucidation of early CNS development
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