About the Project
The recent technological advancement of bioinformatics, next-generation sequencing and live imaging has transformed medical research. By combining these multidisciplinary approaches together, this project aims to understand the cellular and molecular mechanism underlying a congenital craniofacial malformation.
The development of the head is a remarkably dynamic and intricate process, requiring the tightly regulated growth, migration and patterning of a particular cell population, cranial neural crest cells (CNCs). For this reason, craniofacial malformations are among the most common, accounting for one third of human congenital defects. Whilst the causes of most cases are unknown, several clinical studies reported the mutations within Alx homeobox genes in recessive hereditary cases (ALX-related frontonasal dysplasia; ALX-FND). Our lab has recently reported a novel function of alx1 gene, and demonstrated that CNCs migration regulated by alx1 is critical to our head development.
In this project, we will use a zebrafish model of ALX1-FND by generating alx1 null mutant line with CRISPR/Cas9 system. The real-time image analysis of CNCs migration in this mutant will facilitate our understanding of how alx1 controls the development of the head and face. Furthermore, we will purify the migrating CNCs from the mutant by FACS for deep sequencing of transcriptomes. Bioinformatics analysis from this targeted cell population will identify the downstream targets of alx1. By integrating the high-throughput data and the live image profiling of CNCs migration into computer modelling, the project will elucidate how the mutation of alx1 gene leads to ALX1-FND.
In addition to this craniofacial malformation, Alx genes are also related to cancer metastasis. Several studies have recently reported that the increased level of Alx genes is associated with metastasis, but little is known about the molecular role of Alx genes in cancer metastasis. The process of epithelial-mesenchymal transition is likely to be a key link between CNCs migration and cancer metastasis, therefore, the outcome of this project can possibly facilitate the understanding of the process of cancer metastasis as well.
By the end of this programme, the student will have both laboratory (cell and developmental biology) and informatics (transcriptomes and imaging analysis) techniques. These skills are essential for a further step in biomedical research, and training will be provided in the collaboration between three laboratories of biomedical, developmental and computational biology.
http://www.ls.manchester.ac.uk/people/profile/?alias=takahashit
http://www.ls.manchester.ac.uk/people/profile/?alias=rattraym
http://www.ls.manchester.ac.uk/people/profile/?alias=herberts
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on our website www.manchester.ac.uk/mrcdtpstudentships
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
Cetinkaya A, Xiong JR, Vargel İ, Kösemehmetoğlu K, Canter Hİ, Gerdan ÖF, Longo N, Alzahrani A, Camps MP, Taskiran EZ, Laupheimer S, Botto LD, Paramalingam E, Gormez Z, Uz E, Yuksel B, Ruacan Ş, Sağıroğlu MŞ, Takahashi T, Reversade B, Akarsu NA (2016). Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling. Am J Hum Genet. 99:299-317
Dee CT, Szymoniuk CR, Mills PE, Takahashi T (2013). Defective neural crest migration revealed by a Zebrafish model of Alx1-related frontonasal dysplasia. Hum Mol Genet. 22:239-251
Amin S, Donaldson IJ, Zannino DA, Hensman J, Rattray M, Losa M, Spitz F, Ladam F, Sagerström C, Bobola N (2015). Hoxa2 selectively enhances Meis binding to change a branchial arch ground state. Dev Cell. 32:265-277
Honkela A, Peltonen J, Topa H, Charapitsa I, Matarese F, Grote K, Stunnenberg HG, Reid G, Lawrence ND, Rattray M (2015). Genome-wide modeling of transcription kinetics reveals patterns of RNA production delays. Proc Natl Acad Sci U S A. 112:13115-13120
Costa G, Harrington KI, Lovegrove HE, Page DJ, Chakravartula S, Bentley K, Herbert SP (2016). Asymmetric division coordinates collective cell migration in angiogenesis. Nat Cell Biol. 18:1292-1301
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