Tgf beta signaling acts on a Hox response element to confer specificity and diversity to Hox protein function

Stanford University, Palo Alto, California, United States
Development (Impact Factor: 6.27). 12/2003; 130(22):5445-55. DOI: 10.1242/dev.00760
Source: PubMed

ABSTRACT Hox proteins play fundamental roles in generating pattern diversity during development and evolution, acting in broad domains but controlling localized cell diversification and pattern. Much remains to be learned about how Hox selector proteins generate cell-type diversity. In this study, regulatory specificity was investigated by dissecting the genetic and molecular requirements that allow the Hox protein Abdominal A to activate wingless in only a few cells of its broad expression domain in the Drosophila visceral mesoderm. We show that the Dpp/Tgfbeta signal controls Abdominal A function, and that Hox protein and signal-activated regulators converge on a wingless enhancer. The signal, acting through Mad and Creb, provides spatial information that subdivides the domain of Abdominal A function through direct combinatorial action, conferring specificity and diversity upon Abdominal A activity.

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    ABSTRACT: Homeodomain (HD) proteins are a large family of evolutionarily conserved transcription factors (TFs) having diverse developmental functions, often acting within the same cell types, yet many members of this family paradoxically recognize similar DNA sequences. Thus, with multiple family members having the potential to recognize the same DNA sequences in cis-regulatory elements, it is difficult to ascertain the role of an individual HD or a subclass of HDs in mediating a particular developmental function. To investigate this problem, we focused our studies on the Drosophila embryonic mesoderm where HD TFs are required to establish not only segmental identities (such as the Hox TFs), but also tissue and cell fate specification and differentiation (such as the NK-2 HDs, Six HDs and identity HDs (I-HDs)). Here we utilized the complete spectrum of DNA binding specificities determined by protein binding microarrays (PBMs) for a diverse collection of HDs to modify the nucleotide sequences of numerous mesodermal enhancers to be recognized by either no or a single subclass of HDs, and subsequently assayed the consequences of these changes on enhancer function in transgenic reporter assays. These studies show that individual mesodermal enhancers receive separate transcriptional input from both I-HD and Hox subclasses of HDs. In addition, we demonstrate that enhancers regulating upstream components of the mesodermal regulatory network are targeted by the Six class of HDs. Finally, we establish the necessity of NK-2 HD binding sequences to activate gene expression in multiple mesodermal tissues, supporting a potential role for the NK-2 HD TF Tinman (Tin) as a pioneer factor that cooperates with other factors to regulate cell-specific gene expression programs. Collectively, these results underscore the critical role played by HDs of multiple subclasses in inducing the unique genetic programs of individual mesodermal cells, and in coordinating the gene regulatory networks directing mesoderm development.
    PLoS ONE 07/2013; 8(7):e69385. DOI:10.1371/journal.pone.0069385 · 3.53 Impact Factor
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    ABSTRACT: eLife digest In all animals, it is important that cells are correctly organised into tissues and organs. This organisation starts in the embryo, and cells are instructed to perform different roles depending on their position within the body. A family of proteins called the Hox proteins coordinates the organisation of the cells in the animal embryo by binding to and controlling the expression of specific genes. To properly control their target genes, Hox proteins need to interact with other proteins called transcription factors that can also bind to the genes. However, only a few of these transcription factors have been identified so far, and it is not clear how Hox proteins are able to interact with them. Here, Baëza, Viala, Heim et al. identified several more transcription factors that can bind to the Hox proteins in fruit fly embryos. The experiments show that Hox proteins are able to bind to many transcription factors that are very different from each other. Baëza, Viala, Heim et al. also show that two short sections within the Hox proteins known as short linear motifs are important for controlling these interactions. A fly Hox protein that was missing these motifs was able to interact with new transcription factors. This inhibitory role was found in Hox proteins from mice and sea anemones, suggesting that these motifs may play the same role in all animals. Baëza, Viala, Heim et al.'s findings challenge the traditional view of the role of the short linear motifs in interactions between proteins. Also, the findings provide an alternative explanation for how the Hox proteins are only able to interact with particular transcription factors in animal embryos. The next step will be to find out whether the inhibitory role of short linear motifs could more generally apply to many other protein families. DOI:
    eLife Sciences 04/2015; 4. DOI:10.7554/eLife.06034 · 8.52 Impact Factor
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    ABSTRACT: Hox genes are a group of genes that specify structures along the anteroposterior axis in bilaterians. Although in many cases they do so by modifying a homologous structure with a different (or no) Hox input, there are also examples of Hox genes constructing new organs with no homology in other regions of the body. Hox genes determine structures though the regulation of targets implementing cellular functions and by coordinating cell behavior. The genetic organization to construct or modify a certain organ involves both a genetic cascade through intermediate transcription factors and a direct regulation of targets carrying out cellular functions. In this review I discuss new data from genome-wide techniques, as well as previous genetic and developmental information, to describe some examples of Hox regulation of different cell functions. I also discuss the organization of genetic cascades leading to the development of new organs, mainly using Drosophila melanogaster as the model to analyze Hox function.
    01/2013; 2013:738257. DOI:10.1155/2013/738257

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