Epigenetic temporal control of mouse Hox genes in vivo

During vertebrate development, the temporal control of Hox gene transcriptional activation follows the genomic order of the genes within the Hox clusters. Although it is recognized that this "Hox clock" serves to coordinate body patterning, the underlying mechanism remains elusive. We have shown that successive Hox gene activation in the mouse embryo is closely associated with a directional transition in chromatin status, as judged by the dynamic progression of transcription-competent modifications: Increases in activation marks correspond to decreases in repressive marks. Furthermore, using a mouse in which a Hox cluster was split into two pieces, we document the necessity to maintain a clustered organization to properly implement this process. These results suggest that chromatin modifications are important parameters in the temporal regulation of this gene family

A Genetic Approach to the Recruitment of PRC2 at the HoxD Locus

Polycomb group (PcG) proteins are essential for the repression of key factors during early development. In Drosophila, the polycomb repressive complexes (PRC) associate with defined polycomb response DNA elements (PREs). In mammals, however, the mechanisms underlying polycomb recruitment at targeted loci are poorly understood. We have used an in vivo approach to identify DNA sequences of importance for the proper recruitment of polycomb proteins at the HoxD locus. We report that various genomic re-arrangements of the gene cluster do not strongly affect PRC2 recruitment and that relatively small polycomb interacting sequences appear necessary and sufficient to confer polycomb recognition and targeting to ectopic loci. In addition, a high GC content, while not sufficient to recruit PRC2, may help its local spreading. We discuss the importance of PRC2 recruitment over Hox gene clusters in embryonic stem cells, for their subsequent coordinated transcriptional activation during development

Duplications of hox gene clusters and the emergence of vertebrates

The vertebrate body plan is characterized by an increased complexity relative to that of all other chordates and large-scale gene amplifications have been associated with key morphological innovations leading to their remarkable evolutionary success. Here, we use compound full Hox clusters deletions to investigate how Hox genes duplications may have contributed to the emergence of vertebrate-specific innovations. We show that the combined deletion of HoxA and HoxB leads to an atavistic heart phenotype, suggesting that the ancestral HoxA/B cluster was co-opted to help in diversifying the complex organ in vertebrates. Other phenotypic effects observed seem to illustrate the resurgence of ancestral (plesiomorphic) features. This indicates that the duplications of Hox clusters were associated with the recruitment or formation of novel cis-regulatory controls, which were key to the evolution of many vertebrate features and hence to the evolutionary radiation of this group

Genetic interaction between Wnt/β-catenin and BMP receptor signaling during formation of the AER and the dorsal–ventral axis in the limb

By conditional gene ablation in mice, we found that β-catenin, an essential downstream effector of canonical Wnt signaling, is a key regulator of formation of the apical ectodermal ridge (AER) and of the dorsal–ventral axis of the limbs. By generation of compound mutants, we also show that β-catenin acts downstream of the BMP receptor IA in AER induction, but upstream or parallel in dorsal–ventral patterning. Thus, AER formation and dorsal–ventral patterningof limbs are tightly controlled by an intricate interplay between Wnt/β-catenin and BMP receptor signaling

A regulatory archipelago controls hox genes transcription in digits

The evolution of digits was an essential step in the success of tetrapods. Among the key players, Hoxd genes are coordinately regulated in developing digits, where they help organize growth and patterns. We identified the distal regulatory sites associated with these genes by probing the three-dimensional architecture of this regulatory unit in developing limbs. This approach, combined with in vivo deletions of distinct regulatory regions, revealed that the active part of the gene cluster contacts several enhancer-like sequences. These elements are dispersed throughout the nearby gene desert, and each contributes either quantitatively or qualitatively to Hox gene transcription in presumptive digits. We propose that this genetic system, which we call a "regulatory archipelago," provides an inherent flexibility that may partly underlie the diversity in number and morphology of digits across tetrapods, as well as their resilience to drastic variations. PAPERFLICK

A model for PRC2 recruitment.

<p>In a first phase, PRC2 is tethered to a particular combination of low affinity PREs. Once bound, the surrounding GC density becomes important for stabilizing or strengthening the binding to target DNA. Internal deletions do not alter the general landscape. Deletion of the borders of the epigenetic domain do not lead to PcG leakage due to the translocation of the 3′ breakpoint into sequences of low or average GC density. Similar results are observed when transgenic constructs are introduced randomly into the genome.</p

The Interplay between Nutrition, Innate Immunity, and the Commensal Microbiota in Adaptive Intestinal Morphogenesis

The gastrointestinal tract is a functionally and anatomically segmented organ that is colonized by microbial communities from birth. While the genetics of mouse gut development is increasingly understood, how nutritional factors and the commensal gut microbiota act in concert to shape tissue organization and morphology of this rapidly renewing organ remains enigmatic. Here, we provide an overview of embryonic mouse gut development, with a focus on the intestinal vasculature and the enteric nervous system. We review how nutrition and the gut microbiota affect the adaptation of cellular and morphologic properties of the intestine, and how these processes are interconnected with innate immunity. Furthermore, we discuss how nutritional and microbial factors impact the renewal and differentiation of the epithelial lineage, influence the adaptation of capillary networks organized in villus structures, and shape the enteric nervous system and the intestinal smooth muscle layers. Intriguingly, the anatomy of the gut shows remarkable flexibility to nutritional and microbial challenges in the adult organism