Attenuated sensing of SHH by Ptch1 underlies evolution of bovine limbs

Guillaume Andrey, Denis Duboule, Dagmar Iber, Jing Liu
Nature Publishing Group, 2014
Article

The large spectrum of limb morphologies reflects the wide evolutionary diversification of the basic pentadactyl pattern in tetrapods. In even-toed ungulates (artiodactyls, including cattle), limbs are adapted for running as a consequence of progressive reduction of their distal skeleton to symmetrical and elongated middle digits with hoofed phalanges. Here we analyse bovine embryos to establish that polarized gene expression is progressively lost during limb development in comparison to the mouse. Notably, the transcriptional upregulation of the Ptch1 gene, which encodes a Sonic hedgehog (SHH) receptor, is disrupted specifically in the bovine limb bud mesenchyme. This is due to evolutionary alteration of a Ptch1 cis-regulatory module, which no longer responds to graded SHH signalling during bovine handplate development. Our study provides a molecular explanation for the loss of digit asymmetry in bovine limb buds and suggests that modifications affecting the Ptch1 cis-regulatory landscape have contributed to evolutionary diversification of artiodactyl limbs.

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Guillaume Andrey, Denis Duboule, Dagmar Iber, Jing Liu
Nature Publishing Group, 2014
Article

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https://infoscience.epfl.ch/record/200491?ln=fr

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Concepts associés

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Publications associées (12)

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Mammalian TOR as a central modulator of the transcriptional response of keratinocyte stem cells to small temperature variations

Fahd Azzabi Zouraq

Being in the layer at the interface of the body with the outside world, keratinocyte stem cells constantly adapt and respond to environmental cues such as temperature and oxygen. However, until now, experiments involving temperature have only examined cold and heat shocks. Here, our work illustrates that small variations of temperature (~1°C) are enough to affect colony size of keratinocyte stem cells and alter expression of some genes involved in various signalling pathways. The promoter regions of the temperature sensitive genes share a sequence located in some Alu short interspersed nuclear elements (Alu SINEs). This sequence termed TORRID contains several IFHL-like motifs (IFHL motif is related to ribogenesis in yeast) and interestingly a minimal TORRID sequence might be enough for a gene to acquire temperature sensitivity. Our findings demonstrated that the expression of temperature sensitive genes is regulated through the mammalian target of rapamycin (mTOR) pathway. The transcription factors ILF1 and RAP1, and histone deacetylase II (HDAC2) –human orthologs of yeast Fhl1p, Rap1 and Rpd3 respectively– associate with TORRID sequences. Small variations of temperature were enough to alter this association. Moreover, mTOR can translocate to the nucleus and associate with the TORRID sequences in a rapamycin and temperature dependent manner. Furthermore, Raptor and Rictor, members of the mTOR complexes 1 and 2 are also involved in this binding. Hence, our results reveal not only that TOR transcriptional activity is evolutionary conserved from yeast to human, but also that a small variation in temperature represents a new input to the mTOR pathway and fine-tune regulation of transcription through TORRID sequences. These results shed new light on the role of Alus in gene regulation.

EPFL2008

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Inversion-induced disruption of the Hoxd cluster leads to the partition of regulatory landscapes

Denis Duboule

The developmental regulation of vertebrate Hox gene transcription relies on the interplay between local and long-range controls. To study this complex genomic organization, we designed a strategy combining meiotic and targeted recombinations to induce large chromosomal rearrangements in vivo without manipulating embryonic stem cells. With this simple approach (called STRING), we engineered a large 7-cM inversion, which split the Hoxd cluster into two independent pieces. Expression analyses showed a partition of global enhancers, allowing for their precise topographic allocation on either side of the cluster. Such a functional organization probably contributed to keeping these genes clustered in the course of vertebrate evolution. This approach can be used to study the relationship between genome architecture and gene expression, such as the effects of genome rearrangements in human diseases or during evolution.

2005

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Long-range enhancer-promoter interactions in the HoxD complex

Denis Duboule

Collinear expression of 5′ Hoxd genes during mammalian limb development is required to properly determine digits number and identity. We recently proposed a two-step model to account for the underlying regulatory mechanism, which involves an initial looping and recognition of the cluster by a complex of enhancer sequences, followed by a micro-scanning of nearby-located genes. This model could account for both the wild-type dosage of the various Hoxd transcripts, as well as for their quantitative variations in several mutant strains. Here, using the Chromosome Conformation Capture (3C) technique, we confirm the initial looping step by showing that the 5′ extremity of the HoxD cluster physically interacts with two previously identified, remote regulatory sequences displaying enhancer activity in developing digits. This spatial conformation is specific to presumptive digits and is not observed in tissues devoid of Hox gene transcription. The flexibility of these long-range interactions is illustrated by the ability of the enhancers to activate reporter transgenes inserted at various positions along the locus. To further define this regulatory landscape, we produced a large chromosomal inversion, separating the reporter transgene from the digit enhancers and HoxD cluster. Surprisingly, this configuration fails to abolish the transgene expression in developing digits, but leads to a major down-regulation of Hoxd genes in this domain, and concurrent morphological defects. These results suggest that the transcriptional activation of Hoxd genes requires the activity of additional and distant regulatory sequences, in addition to the enhancers identified so far by transgenic analysis.

Elsevier Science BV2009

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