I am interested in the molecular mechanisms that regulate embryonic development of the forebrain. We study these mechanisms using a wide range of techniques, including the generation and analysis of genetically modified mice.
Understanding how the brain develops will give us important insights into how neurodevelopmental disorders arise, and, ultimately, how they may be treated. In collaboration with David Price and Thomas Theil, we have investigated the roles played by the transcription factors Pax6, Foxg1 and Gli3 in controlling embryonic development of the forebrain. Each of these factors is a high-level regulator of the complex transcriptional networks of gene expression that control neural development. Using next generation sequencing techniques and bioinformatic analysis (collaboration with Ian Simpson, School of Informatics) we are attempting to unravel these gene networks, to help us understand their function. We have recently shown that Pax6 controls the rate at which neural progenitor cells divide, through a pathway involving cdk6 and the tumour suppressor protein pRb.
Newly formed neurons in the embryonic brain must make appropriate connections with each other, in order for the brain to function correctly. To help us understand how these wiring patterns become established, we have been looking at the function of heparan sulphate (HS), a complex sugar molecule found on the surface of most animal cells. We have found that surprisingly small chemical changes in HS have big effects on wiring patterns, consistent with a ‘sugar code’ that helps guide axons to their correct target in the developing brain. This project is a collaboration with Tom Pratt (Edinburgh) and Jerry Turnbull (Liverpool).
I also have a long standing interest in the role played by Wnt signalling during development of the CNS. We are exploring how Wnt influences neural differentiation of embryonic stem (ES) cells, in collaboration with Norshariza Nordin (Malaysia). We have also investigated how Wnt signalling influences development of the cerebellum, and how a type of childhood brain tumour known as medulloblastoma may arise when Wnt signalling in the cerebellum goes awry.
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Mi, D., Carr, C.B., Georgala, P.A., Huang Y-T., Manuel, M.N., Jeanes, E., Niisato, E., Sansom, S.N., Livesey, F.J., Theil, T., Hasenpusch-Theil, K., Simpson, T.I, Mason, J.O. and Price, D.J. (2013) Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of pRb Neuron 78: 269-284
Amaniti, E.M., Hasenpusch-Theil, K., Li, Z., Magnani, D., Kessaris, N., Mason, J.O. and Theil, T. (2013) Gli3 is required in Emx1+ progenitors for the development of the corpus callosum Developmental Biology 376: 113-124
Selvadurai, H. and Mason, J.O. (2012) Activation of Wnt/?-catenin signalling affects differentiation of cells arising from the cerebellar ventricular zone PLoS One 7(8): e42572 doi:10.1371/journal.pone.0042572
Pratt, T., Davey, J.W., Nowakowski, T.J., Raasumaa, C., Rawlik, K.C., McBride, D., Clinton, M., Mason, J.O. and Price, D.J. (2012) The expression and activity of beta-catenin in the thalamus and its projections to the cerebral cortex. BMC Neuroscience 13:20
Conway, C.D., Price, D.J., Pratt, T. and Mason, J.O. (2011) Analysis of axon guidance defects in heparan sulphate sulphotransferase compound mutant mice Journal of Anatomy 219: 734-742
Selvadurai, H. and Mason, J.O. (2011) Wnt/?-catenin Signalling is Active in a Highly Dynamic Pattern During Development of the Mouse Cerebellum. PLoS One 6(8): e23012. doi:10.1371/journal.pone.0023012
Fotaki, V., Price, D.J. and Mason, J.O. (2011) Wnt/β-catenin signalling is disrupted in the extratoes (Gli3Xt/Xt) mutant from early stages of forebrain development, concomitant with anterior neural plate patterning defects J. Comp. Neurol. 9: 1640-1657
Manuel, M.N., Martynoga, B.S., Molinek, M.D., Quinn, J.C., Kroemmer, C., Mason, J.O. and Price, D.J. (2011) The transcription factor Foxg1 regulates telencephalic progenitor proliferation cell autonomously, in part by controlling Pax6 expression levels Neural Development 6:9
Conway, C.D., Howe, K., Nettleton, N., Price, D.J., Mason, J.O. and Pratt, T. (2011) Heparan sulphate sugar modifications mediate the functions of Slits and other factors needed for mouse forebrain commissure development. J. Neuroscience 31: 1955-1970 Quinn, J.C., Molinek, M., Nowakowski, T.J., Mason, J.O. and Price, D.J. (2010) Novel lines of Pax6-/- embryonic stem cells exhibit reduced neurogenic capacity without loss of viability BMC Neuroscience 11:26
Manuel, M., Martynoga, B.S., Yu, T., West, J.D., Mason, J.O. and Price, D.J. (2010) The transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice. Development 137: 487-97
Fotaki, V., Larralde, O., Zeng, S., McLaughlin, D., Nichols, J., Price, D.J., Theil, T. and Mason, J.O. (2010) Loss of Wnt8b has no overt effect on hippocampus development but leads to altered Wnt gene expression levels in dorsomedial telencephalon. Developmental Dynamics 239: 284-296
This article was published on Sep 9, 2013