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Molecular regulators of stem and progenitor cell fate

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

Project Description

Using modern technology such as TALLEN and CRISPR/Cas site-directed mutagenesis in cell lines as well as zebrafish, we use loss- and gain-of-function analysis to unravel the role of molecular regulators such as DEF6, SWAP70, ID4 and LYL1 in stem and progenitor cell fate determination. We have recently shown that DEF6, which plays a vital role in T cell-mediated autoimmunity, is associated with P-bodies (Hey et al., 2012) suggesting a role in translational control of mRNAs. During early zebrafish embryogenesis, DEF6 and its only relative SWAP70 are crucial for cell movements during gastrulation linking non-canonical Wnt signaling and Rho GTPase activity (Goudevenou et al., 2011, Xu et al., 2014). ID4 that acts as a tumour suppressor in acute myeloid leukaemia and chronic lymphocytic leukaemia (Chen et al., 2011) also promotes osteoblast differentiation potentially making it a target for preventing onset of senile osteoporosis (Tokuzawa et al., 2010). In addition, ID4 regulates mammary development by supressing p38MAPK activity (Dong et al., 2010) and based on earlier work (Bedford et al., 2005) we are currently determining the molecular mechanisms underlying ID4 function during neural stem cell proliferation and differentiation in zebrafish. LYL1 is required for foetal and adult hematopoietic stem cell functions and B-cell differentiation (Capron et al., 2006), for the formation of newly formed blood vessels in adulthood (Pirot et al., 2010). LYL1-deficiency induces a stress erythropoiesis (Capron et al., 2011) and adult haematopoietic stem cells require LYL1 for survival (Souroullas et al., 2009) and we are currently establishing zebrafish mutants to determine LYL1 function in early and late haematopoietic stem cell fate.

Postgraduate students will be part of the on-going research programme outlined above benefitting from the excellent research environment in the School of Life Sciences and related Schools within the University of Nottingham with a vibrant postgraduate student community. The PGR student will be trained in and utilise state-of-the-art technology such as FACS, Next Generation Sequencing, Advanced Microscopy and Live Cell Imaging all available within the School of Life Sciences. The PGR student will also greatly benefit from expert supervision and support throughout the PGR programme providing an excellent base for a future career in science.

Funding Notes

Home and EU applicants should contact the supervisor to determine the current funding status for this project. International applicants should visit our page for information regarding fees and funding at the University http://www.nottingham.ac.uk/studywithus/international-applicants/scholarships-fees-and-finance/scholarships/index.aspx

References

BEDFORD, L., WALKER, R., KONDO, T., VAN CRÜCHTEN, I., KING, E. R. and SABLITZKY, F., 2005. Id4 is required for the correct timing of neural differentiation Developmental Biology. 280(2), 386-395
• CAPRON, C., LÉCLUSE, Y., KAUSHIK, A. L., FOUDI, A., LACOUT, C., SEKKAI, D., GODIN, I., ALBAGLI, O., POULLION, I., SVINARTCHOUK, F., SCHANZE, E., VAINCHENKER, W., SABLITZKY, F., BENNACEUR-GRISCELLI, A. and DUMÉNIL, D., 2006. The SCL relative LYL-1 is required for fetal and adult hematopoietic stem cell function and B-cell differentiation Blood. 107(12), 4678-4686
• CAPRON, C., LACOUT, C., LÉCLUSE, Y., WAGNER-BALLON, O., KAUSHIK, A.L., CRAMER-BORDÉ, E., SABLITZKY, F., DUMÉNIL, D. and VAINCHENKER, W., 2011. LYL-1 deficiency induces a stress erythropoiesis. Experimental Hematology. 39(6), 629-642
• CHEN, S.-S., CLAUS, R., LUCAS, D.M., YU, L., QIAN, J., RUPPERT, A.S., WEST, D.A., WILLIAMS, K.E., JOHNSON, A.J., SABLITZKY, F., PLASS, C. and BYRD, J.C., 2011. Silencing of the inhibitor of DNA binding protein 4 (ID4) contributes to the pathogenesis of mouse and human CLL Blood. 117(3), 862-871
• DONG, J, HUANG, S., CAIKOVSKI, M., JI, S., MCGRATH, A., CUSTORIO, M.G., CREIGHTON, C.J., MALIAKKAL, P., BOGOSLOVSKAIA, E., DU, Z., ZHANG, X., LEWIS, M.T., SABLITZKY, F., BRISKEN, C. and LI, Y., 2011. ID4 regulates mammary gland development by suppressing p38MAPK activity Development. 138, 5247-5256
• GOUDEVENOU, K., MARTIN, P., YEH, Y-J., JONES, P. and SABLITZKY, F., 2011. Def6 is required for convergent extension movements during zebrafish gastrulation downstream of Wnt5b signaling PLoS One. 6(10), e26548
• HEY, F., CZYZEWICZ, N., JONES, P. and SABLITZKY, F., 2012. DEF6, a novel substrate for the Tec kinase ITK, contains a glutamine-rich aggregation-prone region and forms cytoplasmic granules that co-localise with P-bodies The Journal of Biological Chemistry. 287(37), 31073-31084
• PIROT, N., DELEUZE, V., EL-HAJJ, R., DOHET, C., SABLITZKY, F., COUTTET, P., MATHIEU, D. and PINET, V., 2010. LYL activity is required for the maturation of newly formed blood vessels in adulthood Blood. 115(25), 5270-5279
• SOUROULLAS, G.P., SALMON, J.M., SABLITZKY, F., CURTIS, D.J. and GOODELL, M.A., 2009. Adult hematopoietic stem and progenitor cells require either Lyl1 or Scl for survival Cell Stem Cell. 4(2), 180-186

How good is research at University of Nottingham in Biological Sciences?

FTE Category A staff submitted: 90.86

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