Identification of a distant<i>cis</i>‐regulatory element controlling pharyngeal arch‐specific expression of zebrafish<i>gdf6a/radar</i>

Reed, Nykolaus P.; Mortlock, Douglas P.

doi:10.1002/dvdy.22251

Cited by 15 publications

(32 citation statements)

References 60 publications

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“…17 This domain conservation, coupled with percent identity and percent similarity, supports the notion that Zfp608 and Zfp609 evolved from a common ancestral gene. 18,19 Expression and function of ancestrally related genes may change through evolution or may remain redundant with similar function. ZORI thymocytes constitutively express Zfp608 and reduced levels of Rag .…”

Section: Resultsmentioning

confidence: 99%

“…The transcriptional start site and Zfp609 promoter were identified using multispecies conservation. 19 The Zfp609 promoter was cloned into a luciferase reporter vector and introduced into VL3-3M2 thymocytes by transient transfection with or without a Zfp608 expression vector. Co-transfection of the Zfp608 expression vector with the Zfp609 promoter luciferase reporter led to a reduction of Zfp609 promoter activity (Figure 6a).…”

Section: Resultsmentioning

confidence: 99%

“…This high level of shared identity supports the notion that Zfp608 and Zfp609 genes evolved from a common ancestral gene. 17–19 The expression and function of ancestrally related genes may change through evolution or may remain redundant. Therefore, we hypothesized that Zfp609 may also regulate Rag gene expression during T-cell development.…”

Section: Introductionmentioning

confidence: 99%

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Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

et al. 2012

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Recombination-activating gene 1 (Rag1) and Rag2 enzymes are required for T cell receptor assembly and thymocyte development. The mechanisms underlying the transcriptional activation and repression of Rag1 and Rag2 are incompletely understood. The zinc-finger protein, Zfp608, represses Rag1 and Rag2 expression when expressed in thymocytes blocking T-cell maturation. Here we show that the related zinc-finger protein, Zfp609, is necessary for Rag1 and Rag2 expression in developing thymocytes. Zfp608 represses Rag1 and Rag2 expression indirectly by repressing the expression of Zfp609. Thus, the balance of Zfp608 and Zfp609 plays a critical role in regulating Rag1 and Rag2 expression, which may manifest itself not only during development of immature thymocytes into mature T cells but also in generation of the T-cell arm of the adaptive immune system, which does not fully develop until after birth.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

et al. 2012

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“…Furthermore, the distant regulatory elements previously identified for GDF6 [80], [81], [82] represent excellent candidate regions for future de novo variant detection. Other candidate genes, such as low density lipoprotein receptor-related protein 6 (LRP6) present within the chromosome 12 candidate interval could also be investigated as LRP6, when specifically deleted from early mesenchyme, causes a slight delay in mouse skull ossification [83].…”

Section: Discussionmentioning

confidence: 99%

Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates

et al. 2013

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Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

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“…In the zebrafish fry, two cartilaginous joints in the head have been studied extensively: the jaw joint between the Meckel's and palatoquadrate cartilages and the bipartite hyoid joint between the ceratohyal, interhyal, and hyosymplectic cartilages (Figure (a)). Studies of these joints have revealed conserved roles for GDF family ligands and new roles for Nkx3.2 and Irx family transcription factors. Contrary to previous dogma, a recent study also suggests that fishes have synovial‐like lubricating joints, particularly in their jaw and fins .…”

Section: Use Of Zebrafish For Developmental Studies Of Jointsmentioning

confidence: 99%

Building and maintaining joints by exquisite local control of cell fate

Smeeton

Askary

Crump

2016

WIREs Developmental Biology

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We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid-filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an “interzone” region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints.

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Identification of a distantcis‐regulatory element controlling pharyngeal arch‐specific expression of zebrafishgdf6a/radar

Cited by 15 publications

References 60 publications

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

Reciprocal regulation of Rag expression in thymocytes by the zinc-finger proteins, Zfp608 and Zfp609

Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates

Building and maintaining joints by exquisite local control of cell fate

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