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The role of the spliceosome protein Prpf8 in embryonic development

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Errors that occur during cardiac development cause congenital heart defects (CHD). Despite the prevalence of CHD, the developmental processes that ensure the heart forms correctly are still being elucidated. We will contribute to the understanding of cardiac development by investigating the function of the spliceosome gene Prpf8, and its links to cilia function, during embryonic heart development. A loss of PRPF8 causes reduced cilia motility at the embryonic node, resulting in errors in the left-right specification of the heart. Additional cardiac morphological defects are present in Prpf8 mutants, consistent with abnormalities in cardiac primary cilia. The abnormal function of cardiac primary cilia has been linked to disruptions in a variety of cardiac developmental processes, including altered cell proliferation and abnormal cardiac morphology. In this project we will determine how PRPF8 dysfunction results in aberrant cardiac development, revealing developmental pathways critical for heart formation, which are likely to be disrupted in human CHD patients.

The function of PRPF8 during cardiac development is of particular interest because PRPF8 mutations have direct associations with human congenital heart defects. The discovery of deleterious variants in PRPF8 in CHD patients suggests a requirement for PRPF8 in human cardiac development. The CHD variants may disrupt PRPF8 function in the spliceosome or cilium resulting in errors in heart formation. The precise mechanisms by which PRPF8 mutations affect cardiac development are yet unknown, and we propose to investigate links between PRPF8 function, cilia, and cardiac disease within this project.

Training/techniques to be provided:
Training in developmental biology techniques such as histology, immunohistochemistry and immunofluorescence, in situ hybridisation, and mouse embryo dissection will be provided. Training in standard molecular biology techniques such as PCR, DNA sequencing, and expression analysis will also be provided. In addition to wet lab skills, the student will gain an understanding of the use of informatics databases such as the genome browser and mutation prediction software as part of the project.

Entry Requirements:
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in a related area / subject. Candidates with experience in developmental biology or genetics are encouraged to apply.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk

Funding Notes

Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Robson A, Makova SZ, Barish S, Zaidi S, Mehta S, Drozd J, Jin SC, Gelb BD, Seidman CE, Chung WK, Lifton RP, Khokha MK, Brueckner M. Histone H2B monoubiquitination regulates heart development via epigenetic control of cilia motility. Proc Natl Acad Sci U S A. 2019 Jul 9;116(28):14049-14054.

Chaudhry B, Henderson DJ. Cilia, mitochondria, and cardiac development. J Clin Invest. 2019 Jun 17;129(7):2666-2668. doi: 10.1172/JCI129827. eCollection 2019 Jun 17.

Ridge LA, Mitchell K, Al-Anbaki A, Qureshi WMS, Stephen LA, Tenin G, Lu Y, Lupu I-E, Clowes C, Robertson A, Barnes E, Wright JA, Keavney B, Ehler E, Lovell SC, Kadler KE, Hentges KE. (2017) Non-muscle Myosin IIB (Myh10) Is Required for Epicardial Function and Coronary Vessel Formation During Mammalian Development. PLoS Genetics, 13(10):e1007068.

Koefoed K, Veland IR, Pedersen LB, Larsen LA, Christensen ST. Cilia and coordination of signaling networks during heart development. Organogenesis. 2014 Jan 1;10(1):108-25. doi: 10.4161/org.27483.

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