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(BBSRC DTP) How is our head formed? – alx1 homeobox gene and craniofacial development


Project Description

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=herberts
http://www.ls.manchester.ac.uk/people/profile/?alias=takahashit
http://www.ls.manchester.ac.uk/people/profile/?alias=rattraym

Entry Requirements:
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.

Funding Notes

This project is to be funded under the BBSRC 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 the BBSRC DTP 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

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 IM, Graham A, Richardson J, Depew MJ, Holland PWH and 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

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