![]() ![]() In the case of RA signaling, Hox genes are direct transcriptional targets of retinoids, and their response to RA signaling involves retinoic acid response elements (RAREs) embedded within and adjacent to the Hox clusters. ( B) The restricted domains of Hox expression arise through an integration of signaling molecules such as RA, FGF and WNT, which are expressed in gradients along the embryonic axis. They exhibit spatial and temporal collinearity, such that 3′ Hox genes are expressed early in development as well as more anteriorly in an embryo generating nested domains of expression as depicted in the drawing of an E10 mouse embryo. ( A) In mammals, there are four clusters of Hox genes, each on different chromosomes. The mammalian Hox gene clusters and the conserved signaling pathways that play a role in defining the Hox gene expression profiles. ![]() Hence, it is important to understand the regulatory mechanisms through which signaling pathways are able to coordinately control the precise patterns of the transcription of the clustered Hox genes required for their roles in specifying diverse morphologic features along the A–P axis. A wide variety of studies in different species and cell culture models have revealed that the nested domains of Hox expression along the A–P axis arise in part through the ability of Hox clusters to integrate and respond to opposing signaling gradients, such as those of Retinoic acid (RA), Fibroblast growth factors (Fgfs) and Wingless related integration sites (WNTs). These nested domains of expression generate a combinatorial Hox code, which provides a molecular framework that serves as a key regulatory step in specifying regional identities and properties of tissues along the A–P axis. Genes in the four mammalian Hox clusters are all transcribed in the same 5′ to 3′ direction with respect to transcription, and the order of Hox genes in each cluster on a chromosome corelates with their temporal and spatial expression domains and functions along the A–P axis of developing embryos ( Figure 1). The clustered Hox genes exhibit an interesting property known as collinearity. Hox genes are known to play key roles in axial patterning and regulating the regional identity of cells and tissues in a wide variety of animals from invertebrates to vertebrates. The highly conserved HOX family of TFs are an example of TFs that are coupled to this ancient GRN. However, the question of how TFs are coupled to these ancient signaling pathways and how they integrate responses to signaling gradients is not fully understood. This suggests that regulatory interactions between signaling pathways and core TFs set up a conserved gene regulatory network (GRN) that guides the formation of the basic body plan and patterning of the A–P axis. Remarkably, despite very different morphologies among chordates, many key TFs and components of major signaling pathways (e.g., Wnts and FGFs), known to regulate developmental processes, have been shown to be similarly aligned along the A–P axis. In chordate evolution, there is emerging evidence for a deeply conserved regulatory network, involving transcription factors (TFs) and signaling pathways, that governs patterning along the anterior–posterior (A–P) body axis. In this review, we summarize some of the recent findings, ideas and emerging mechanisms underlying the regulation of transcription in general and consider how they may be relevant to understanding the transcriptional regulation of Hox genes.Īnimals display remarkable variety in their body plans and there is great interest in understanding the degree to which conserved and distinct mechanisms underlie this diversity in the formation and elaboration of basic body plans in animal evolution. New insights are emerging about the dynamics and molecular mechanisms governing transcriptional regulation, and there is interest in understanding how these may play a role in contributing to the regulation of the expression of the clustered Hox genes. Hence, it is important to understand the regulatory mechanisms that coordinately control the precise patterns of the transcription of clustered Hox genes required for their roles in development. ![]() Nested domains of Hox expression generate a combinatorial code that provides a molecular framework for specifying the properties of tissues along the A–P axis. Hox genes play key roles in axial patterning and regulating the regional identity of cells and tissues in a wide variety of animals from invertebrates to vertebrates. ![]()
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