Abstract
Organogenesis is controlled by gene networks activated by upstream selector genes. During development the gene network is activated stepwise, with a sequential deployment of successive transcription factors and signalling molecules that modify the interaction of the elements of the network as the organ forms. Very little is known about the steps leading from the early specification of the cells that form the organ primordium to the moment when a robust gene network is in place. Here we study in detail how a Hox protein induces during early embryogenesis a simple organogenetic cascade that matures into a complex gene network through the activation of feedback and feed forward interaction loops. To address how the network organization changes during development and how the target genes integrate the genetic information it provides, we analyze in Drosophila the induction of posterior spiracle organogenesis by the Hox gene Abdominal-B (Abd-B). Initially, Abd-B activates in the spiracle primordium a cascade of transcription factors and signalling molecules including the JAK/STAT signalling pathway. We find that at later stages STAT activity feeds back directly into Abd-B, initiating the transformation of the Hox cascade into a gene-network. Focusing on crumbs, a spiracle downstream target gene of Abd-B, we analyze how a modular cis regulatory element integrates the dynamic network information set by Abd-B and the JAK/STAT signalling pathway during development. We describe how a Hox induced genetic cascade transforms into a robust gene network during organogenesis due to the repeated interaction of Abd-B and one of its targets, the JAK/STAT signalling cascade. Our results show that in this network STAT functions not just as a direct transcription factor, but also acts as a "counter-repressor", uncovering a novel mode for STAT directed transcriptional regulation.
Highlights
Organogenesis is controlled by the activation of complex gene regulatory networks in precise positions of the organism [1]
To address how the network organization changes during development and how the target genes integrate the genetic information it provides, we analyze in Drosophila the induction of posterior spiracle organogenesis by the Hox gene Abdominal-B (Abd-B)
The enrichment of input recovery shows that STAT is able to bind directly to the crb enhancer, reinforcing the view that crb is a direct target of the JAK/STAT pathway
Summary
Organogenesis is controlled by the activation of complex gene regulatory networks in precise positions of the organism [1]. Master regulator genes, encode transcription factors required for the expression of entire organogenetic gene regulatory networks and, when expressed ectopically, can induce the formation of additional organs at new locations [2,3]. Prominent examples are Eyeless (Ey) capable of inducing ectopic eyes; or the Hox proteins capable of inducing segment specific organs [1,4]. These genes by themselves are unable to provide all the information required to specify an organ. The organ specified by a particular Hox protein varies at different positions of the segment depending on its interaction with tissue-specific transcription factors and signalling pathway effectors active in each region. CRMs play a critical role since they act as integrators of specific combinations of transregulatory transcription factors and signalling pathway effectors, resulting in localized transcriptional activity
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