Dr T Takahashi, Prof M Rattray, Dr S Herbert
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Watching, listening, eating, thinking - all these vital actions are performed by our head. The head is the most important, complex and characteristic structure in our body. The overall aim of this project is to investigate how our head is formed by combining a laboratory experimental approach with high-throughput bioinformatics analysis.
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 studies reported the mutations within Alx homeobox genes (Alx1, Alx3, Alx4) 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 first establish a zebrafish model of ALX-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 this new alx1 gene regulatory network controlling vertebrate head development.
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 BBSRC Doctoral Training Programme. 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 the BBSRC DTP website http://www.dtpstudentships.manchester.ac.uk/
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
McGonnell I, Graham A, Richardson J, Fish J, Depew M, Dee CT, Holland PW, Takahashi T (2011). Evolution of the Alx homeobox gene family: parallel retention and independent loss of the vertebrate Alx3 gene. Evol Dev. 13:343-351
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
Herbert SP, Cheung JY, Stainier DY (2012). Determination of endothelial stalk versus tip cell potential during angiogenesis by H2.0-like homeobox-1. Curr Biol. 22:1789-1794
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