Shh and Gremlin1 chromosomal landscapes in development and disease

Zeller, Rolf; Zúñiga, Aimée

doi:10.1016/j.gde.2007.07.006

Cited by 13 publications

(19 citation statements)

References 34 publications

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“…In fact, regulatory landscapes with distant and dispersed cis -regulatory regions seem to be a recurring theme in the dynamic spatio-temporal regulation of genes that are essential for limb bud development (reviewed in ref. [2,9,10], see also below).…”

Section: Introductionmentioning

confidence: 98%

Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1expression in mouse limb buds

et al. 2012

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BackgroundMouse limb bud is a prime model to study the regulatory interactions that control vertebrate organogenesis. Major aspects of limb bud development are controlled by feedback loops that define a self-regulatory signalling system. The SHH/GREM1/AER-FGF feedback loop forms the core of this signalling system that operates between the posterior mesenchymal organiser and the ectodermal signalling centre. The BMP antagonist Gremlin1 (GREM1) is a critical node in this system, whose dynamic expression is controlled by BMP, SHH, and FGF signalling and key to normal progression of limb bud development. Previous analysis identified a distant cis-regulatory landscape within the neighbouring Formin1 (Fmn1) locus that is required for Grem1 expression, reminiscent of the genomic landscapes controlling HoxD and Shh expression in limb buds.ResultsThree highly conserved regions (HMCO1-3) were identified within the previously defined critical genomic region and tested for their ability to regulate Grem1 expression in mouse limb buds. Using a combination of BAC and conventional transgenic approaches, a 9 kb region located ~70 kb downstream of the Grem1 transcription unit was identified. This region, termed Grem1 Regulatory Sequence 1 (GRS1), is able to recapitulate major aspects of Grem1 expression, as it drives expression of a LacZ reporter into the posterior and, to a lesser extent, in the distal-anterior mesenchyme. Crossing the GRS1 transgene into embryos with alterations in the SHH and BMP pathways established that GRS1 depends on SHH and is modulated by BMP signalling, i.e. integrates inputs from these pathways. Chromatin immunoprecipitation revealed interaction of endogenous GLI3 proteins with the core cis-regulatory elements in the GRS1 region. As GLI3 is a mediator of SHH signal transduction, these results indicated that SHH directly controls Grem1 expression through the GRS1 region. Finally, all cis-regulatory regions within the Grem1 genomic landscape locate to the DNAse I hypersensitive sites identified in this genomic region by the ENCODE consortium.ConclusionsThis study establishes that distant cis-regulatory regions scattered through a larger genomic landscape control the highly dynamic expression of Grem1, which is key to normal progression of mouse limb bud development.

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Section: Introductionmentioning

confidence: 98%

Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1expression in mouse limb buds

et al. 2012

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“…Our analysis focuses on one of the best-studied vertebrate enhancers, the Z one of Polarizing Activity [ZPA] R egulatory S equence (ZRS, also known as MFCS1) (Lettice et al, 2003; 2008; 2014; 2012; Sagai et al, 2005; 2004; Zeller and Zuniga, 2007). The ZRS is a limb-specific enhancer of the Sonic hedgehog ( Shh ) gene that is located at the extreme distance of nearly one million base pairs from its target promoter.…”

Section: Introductionmentioning

confidence: 99%

Progressive Loss of Function in a Limb Enhancer during Snake Evolution

Kvon

Kamneva

Melo

et al. 2016

Cell

293

285

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The evolution of body shape is thought to be tightly coupled to changes in regulatory sequences, but specific molecular events associated with major morphological transitions in vertebrates have remained elusive. We identified snake-specific sequence changes within an otherwise highly conserved long-range limb enhancer of Sonic hedgehog (Shh). Transgenic mouse reporter assays revealed that the in vivo activity pattern of the enhancer is conserved across a wide range of vertebrates including fish, but not in snakes. Genomic substitution of the mouse enhancer with its human or fish ortholog results in normal limb development. In contrast, replacement with snake orthologs caused severe limb reduction. Synthetic restoration of a single transcription factor binding site lost in the snake lineage reinstated full in vivo function to the snake enhancer. Our results demonstrate changes in a regulatory sequence associated with a major body plan transition and highlight the role of enhancers in morphological evolution.

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“…The ‘GCR’ and ‘Prox’ regions are located at least 200 kb and 45 kb upstream of Hoxd13 , respectively, and regulate the expression of 5′HOXD gene cluster in the presumptive digit territory. Ul: mouse mutation Ulnaless ;37 SPD (synpolydactyly syndromes) marks a human point mutation and a 117 kb microdeletion 40. Orange rectangles represent the 5′HOXD genes ( Hoxd13 to Hox d10 ) expressed under the control of the GCR and Prox regions in limb buds; black rectangles represent the more 3′HOXD genes not controlled by these two cis ‐regulatory regions.…”

Section: Mouse Genetics: Insights Into the Molecular Alterations Thatmentioning

confidence: 99%

The molecular basis of human congenital limb malformations

Zúñiga

Zeller

Probst

2012

WIREs Developmental Biology

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This review focuses predominantly on the human congenital malformations caused by alterations affecting the morphoregulatory gene networks that control early limb bud patterning and outgrowth. Limb defects are among the most frequent congenital malformations in humans that are caused by genetic mutations or teratogenic effects resulting either in abnormal, loss of, or additional skeletal elements. Spontaneous and engineered mouse models have been used to identify and study the molecular alterations and disrupted gene networks that underlie human congenital limb malformations. More recently, mouse genetics has begun to reveal the alterations that affect the often-large cis-regulatory landscapes that control gene expression in limb buds and cause devastating effects on limb bud development. These findings have paved the way to identifying mutations in cis-regulatory regions as causal to an increasing number of congenital limb malformations in humans. In these cases, no mutations in the coding region of a presumed candidate were previously detected. This review highlights how the current understanding of the molecular gene networks and interactions that control mouse limb bud development provides insight into the etiology of human congenital limb malformations.

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Shh and Gremlin1 chromosomal landscapes in development and disease

Cited by 13 publications

References 34 publications

Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1expression in mouse limb buds

Conserved cis-regulatory regions in a large genomic landscape control SHH and BMP-regulated Gremlin1expression in mouse limb buds

Progressive Loss of Function in a Limb Enhancer during Snake Evolution

The molecular basis of human congenital limb malformations

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