Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish

Tong, Xiangjun; Zu, Yao; Li, Wenyuan; Ying, Lingxiao; Yang, Jing; Wang, Xin; He, Shuonan; Li, Da; Zhu, Zuoyan; Chen, Jianming; Lin, Shuo; Zhang, Bo

doi:10.1038/ncomms4153

Cited by 43 publications

(41 citation statements)

References 58 publications

(57 reference statements)

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“…LZTR1 encodes a member of the BTB-Kelch superfamily that is highly expressed in the heart during development and has been associated with Noonan {Yamamoto 2015; Ghedira 2017} and DiGeorge Syndromes {Kurahashi 1995}, both of which are characterized by CHD. KCTD10 binds to and represses the transcriptional activity of TBX5 (T-box transcription factor), which plays a dose-dependent role in the formation of cardiac chambers {Tong 2014}. KCTD10 is highly expressed in the heart during development and has been shown to produce CHD in mice when dysregulated {Ren 2014}.…”

Section: Discussionmentioning

confidence: 99%

Early post-zygotic mutations contribute to congenital heart disease

Hsieh

et al. 2019

Preprint

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53Background 54The contribution of somatic mosaicism, or genetic mutations arising after oocyte fertilization, to congenital 55 heart disease (CHD) is not well understood. Further, the relationship between mosaicism in blood and 56 cardiovascular tissue has not been determined. 58Results 59We developed a computational method, Expectation-Maximization-based detection of Mosaicism (EM-60 mosaic), to analyze mosaicism in exome sequences of 2530 CHD proband-parent trios. EM-mosaic 61 detected 326 mosaic mutations in blood and/or cardiac tissue DNA. Of the 309 detected in blood DNA, 62 85/97 (88%) tested were independently confirmed, while 7/17 (41%) candidates of 17 detected in cardiac 63 tissue were confirmed. MosaicHunter detected an additional 64 mosaics, of which 23/46 (50%) among 58 64 candidates from blood and 4/6 (67%) of 6 candidates from cardiac tissue confirmed. Twenty-five mosaic 65 variants altered CHD-risk genes, affecting 1% of our cohort. Of these 25, 22/22 candidates tested were 66 confirmed. Variants predicted as damaging had higher variant allele fraction than benign variants, 67 suggesting a role in CHD. The frequency of mosaic variants above 10% mosaicism was 0.13/person in 68 blood and 0.14/person in cardiac tissue. Analysis of 66 individuals with matched cardiac tissue available 69 revealed both tissue-specific and shared mosaicism, with shared mosaics generally having higher allele 70 fraction. 72 Conclusions 73We estimate that ~1% of CHD probands have a mosaic variant detectable in blood that could contribute 74 to cardiac malformations, particularly those damaging variants expressed at higher allele fraction 75 compared to benign variants. Although blood is a readily-available DNA source, cardiac tissues analyzed 76 contributed ~5% of somatic mosaic variants identified, indicating the value of tissue mosaicism analyses. 77 78 Keywords 79 Mosaic, Somatic, Congenital Heart Disease, Exome Sequencing 80 2 Background 81 Mosaicism results from somatic mutations that arise post-zygotically in an early embryonic cell, 82 resulting in two or more cell populations with distinct genotypes in the developing embryo {Biesecker 83 2013}. The developmental status of the early embryonic cell at the time of mutagenesis determines the 84 proportion of variant-carrying cells and the tissue distribution of these cells in the post-natal child {Acuna-85 Hidalgo 2015}. While germline variants have a variant allele frequency (VAF) of 0.5, somatic mosaic 86 variants have a significantly lower VAF. 87 Post-zygotic mosaic mutations have been implicated in several diseases including non-malignant 88 developmental disorders such as overgrowth syndromes {Poduri 2013; Lindhurst 2012; Kurek 2016}, 89 structural brain malformations {Poduri 2012; Jamuar 2014; Riviere 2012; Lee 2012}, epilepsy {Stosser 90 2018}, and autism spectrum disorder {Lim 2017; Krupp 2017; Freed 2016; Dou 2017}. Recent analyses 91 also identified mosaic variants in a cohort of patients with congenital heart disease (CHD) {Manheimer 92 2018}, but the prev...

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Section: Discussionmentioning

confidence: 99%

Early post-zygotic mutations contribute to congenital heart disease

Hsieh

et al. 2019

Preprint

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“…HA has been recognized for its role in the formation of the cardiac jelly during heart morphogenesis [26,27,28]. Furthermore, HA can play an important role in angiogenesis and wound healing [12,29].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, injectable cryogels have gained tremendous momentum in the field, as they are syringe-injectable and fully polymerized scaffolds retaining their integrity and properties once introduced into the body. Cryogels display improved mechanical stability when compared to traditional hydrogels, as their unique macrostructure provides increased strength for the gels to undergo compaction and full recovery at the injection site [13,26,31,35]. Additionally, cryogels have been utilized for a variety of biomedical applications, including tissue engineering [44,45,46].…”

Section: Introductionmentioning

confidence: 99%

Injectable Hyaluronic Acid-co-Gelatin Cryogels for Tissue-Engineering Applications

et al. 2018

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Polymeric scaffolds such as hydrogels can be engineered to restore, maintain, or improve impaired tissues and organs. However, most hydrogels require surgical implantation that can cause several complications such as infection and damage to adjacent tissues. Therefore, developing minimally invasive strategies is of critical importance for these purposes. Herein, we developed several injectable cryogels made out of hyaluronic acid and gelatin for tissue-engineering applications. The physicochemical properties of hyaluronic acid combined with the intrinsic cell-adhesion properties of gelatin can provide suitable physical support for the attachment, survival, and spreading of cells. The physical characteristics of pure gelatin cryogels, such as mechanics and injectability, were enhanced once copolymerized with hyaluronic acid. Reciprocally, the adhesion of 3T3 cells cultured in hyaluronic acid cryogels was enhanced when formulated with gelatin. Furthermore, cryogels had a minimal effect on bone marrow dendritic cell activation, suggesting their cytocompatibility. Finally, in vitro studies revealed that copolymerizing gelatin with hyaluronic acid did not significantly alter their respective intrinsic biological properties. These findings suggest that hyaluronic acid-co-gelatin cryogels combined the favorable inherent properties of each biopolymer, providing a mechanically robust, cell-responsive, macroporous, and injectable platform for tissue-engineering applications.

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“…Other family members appear to have very different molecular functions by acting in the regulation of transcription. These include Kctd10, a factor involved in heart development through the inhibition of Tbx5a activity, apparently by direct interaction between the Tbx and Kctd components (Hu et al, 2014; Tong et al, 2014). In addition Kctd10 also interacts with proliferating cell nuclear antigen and through this interaction affects proliferation (Wang et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Genes regulated by potassium channel tetramerization domain containing 15 (Kctd15) in the developing neural crest

Wong¹,

Rebbert²,

Wang³

et al. 2016

Int. J. Dev. Biol.

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Neural crest (NC) development is controlled precisely by a regulatory network with multiple signaling pathways and the involvement of many genes. The integration and coordination of these factors are still incompletely understood. Overexpression of Wnt3a and the BMP antagonist Chordin in animal cap cells from Xenopus blastulae induces a large number of NC specific genes. We previously suggested that Potassium Channel Tetramerization Domain containing 15 (Kctd15) regulates NC formation by affecting Wnt signaling and the activity of transcription factor AP-2. In order to advance understanding of the function of Kctd15 during NC development, we performed DNA microarray assays in explants injected with Wnt3a and Chordin, and identify genes that are affected by overexpression of Kctd15. Among many genes identified we chose Duf domain containing protein 1(ddcp1), Platelet-Derived Growth Factor Receptor a (pdgfra), Complement factor properdin (cfp), Zinc Finger SWIM-Type Containing 5 (zswim5), and complement component 3 (C3) to examine their expression by whole mount in situ hybridization. Our work points to a possible role for Kctd15 in the regulation of NC formation and other steps in embryonic development.

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Kctd10 regulates heart morphogenesis by repressing the transcriptional activity of Tbx5a in zebrafish

Cited by 43 publications

References 58 publications

Early post-zygotic mutations contribute to congenital heart disease

Early post-zygotic mutations contribute to congenital heart disease

Injectable Hyaluronic Acid-co-Gelatin Cryogels for Tissue-Engineering Applications

Genes regulated by potassium channel tetramerization domain containing 15 (Kctd15) in the developing neural crest

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