Project title: Modelling Neural Crest Diseases with Human Pluripotent Stem Cells

Project supervisor: Professor Peter Andrews (BMS and CSCB)

Application deadline: Friday 14 December 2012.

Project description:

Neural crest cells, derived from the border of the neural and non-neural ectoderm of the early embryo, populate a diverse array of tissues during development, including much of the skeleton and musculature of the head, the valves of the heart, the adrenal medulla and the enteric nervous system. The neural crest cells populating these tissues arise from different regions of the anterior posterior axis of the embryo. Many birth defects, and some pediatric cancers such as neuroblastoma, have their origins in the abnormal specification and behaviour of neural crest cell caused by genetic mutations.

Human embryonic stem (ES) cells and induced pluripotent stem (iPS) cells, collectively pluripotent stem cells (PSC), can be induced to differentiate into all somatic cells of the developing embryo, including neural crest cells. They have been used to provide in vitro models for various inherited diseases. Guided by developmental genetics of the mouse and zebra fish, we will develop robust protocols for the differentiation of neural crest cells from human PSC and, determine how neural crest cells corresponding to different regions of the embryonic axis can be specified during human PSC differentiation. Using reporters and by modulating the activity of specific genes with inducible over expression and knockdown systems we will establish the key regulatory pathways that control human neural crest specification.

These data will provide the basis for establishing in vitro models for inherited diseases, such as Hirsprung’s disease, that have their origins in the neural crest, and developing protocols for the treatment of such disease.

References:

• Enver, T., Pera, M.,Peterson, P., Andrews, P.W. 2009
  Stem Cell States, Fates and the Rules of Attraction.  Cell Stem Cell, 4:387 – 397.
• Na, J., Plews, J., Li, J, Wongtrakoongate, P., Tuuri, T., Feki, A., Andrews, P.W. and Unger, C.  2010 
  Molecular mechanisms of pluripotency and reprogramming. 
  Stem Cell Research and Therapy.  1:33 - 40Gokhale PJ, Andrews PW. 2012  The development of pluripotent stem cells.  Curr Opin Genet Dev. 2012 Aug 3. [Epub ahead of print]
• Le Douarin NM, Dupiny E.  2003 
  Multipotentiality of the neural crest. 
  Current Opin. Genet. Devel.  13:529–536

Contact details:

Professor Peter Andrews

Email: P.W.Andrews@sheffield.ac.uk

Web: http://www.shef.ac.uk/bms/research/andrews