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Identification of the Genetic Risks ...

He, Xuan Anita,

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Identification of the Genetic Risks of Craniosynostosis in Zebrafish Model /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Identification of the Genetic Risks of Craniosynostosis in Zebrafish Model // Xuan Anita He.
作者:	He, Xuan Anita,
面頁冊數:	1 electronic resource (166 pages)
附註:	Source: Dissertations Abstracts International, Volume: 85-07, Section: B.
Contained By:	Dissertations Abstracts International85-07B.
標題:	Genetics. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=30816651
ISBN:	9798381431377

Identification of the Genetic Risks of Craniosynostosis in Zebrafish Model /
He, Xuan Anita,

Identification of the Genetic Risks of Craniosynostosis in Zebrafish Model /Xuan Anita He. - 1 electronic resource (166 pages)

Source: Dissertations Abstracts International, Volume: 85-07, Section: B.

Bones of the cranial vault protect the underlying brain but preserve flexibility to allow brain growth. The edges of skull bones are joined by fibrous sutures, which provide structural support and are the sites of bone growth. Craniosynostosis (CS), premature fusion of bones at the sutures, causes skull deformity and secondary problems in brain development. Bone morphogenetic protein (BMP) signaling is critical in regulating osteoblast differentiation and ossification. Several components of the BMP signaling pathway are associated with increased risk of CS, supporting a central role for BMP signaling in suture formation and development of CS. However, the specific factors involved and disease mechanisms remain largely unknown. To address the gaps in our knowledge, we identified regulatory elements active in skeletal tissues associated with the risk of CS. Briefly, we selected conserved noncoding elements within the genomic regions near the CS risk genes, BMP2 and BMPER (BMP Binding Endothelial Regulator), and performed zebrafish transgenesis to screen for enhancer activities in cranial skeletal tissues. We found multiple enhancers that directed transgene expression consistent with the expression of endogenous bmp2 and bmper genes. Using confocal microscopy, we demonstrated activity of the enhancer, -707BMPER, in cartilage closely associated with developing frontal bones, suggesting its involvement in cranial bone growth, suture formation and the risk of CS. We also performed an enhanced yeast one-hybrid (eY1H) assay to determine the transcription factors that interacted with the identified enhancers, implicating the underlying signaling pathways in regulation of their activity. Compelling human genetic evidence has revealed a role for SMAD6 (mothers against decapentaplegic homolog 6), a negative regulator of BMP signaling, in craniosynostosis. SMAD6 mutations are also associated with cardiovascular abnormalities and nonsyndromic radioulnar synostosis. However, there are significant unanswered questions about the mechanisms linking specific SMAD6 mutations to any of these defects. To create a tractable animal model to address these questions, we used CRISPR targeting to mutate the zebrafish ortholog, smad6a and smad6b. In addition, we developed a zebrafish assay to evaluate the functional consequences of SMAD6 sequence variants, based on the ability of Smad6 to disrupt dorsal-ventral patterning of zebrafish embryos in a dose-dependent manner. We anticipate that the zebrafish assay can provide a convenient approach to verify the disease risk of SMAD6 variants, and that zebrafish lacking smad6 function will be a tractable genetic model to study the role of Smad6 in development.

English

ISBN: 9798381431377Subjects--Topical Terms:

530508
Genetics.
Subjects--Index Terms:

Craniofacial disease

Identification of the Genetic Risks of Craniosynostosis in Zebrafish Model /
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