The research of my group focuses on the development of the brain, particularly the cerebral neocortex.
My team takes a multidisciplinary approach, using a range of neuroanatomical, electrophysiological, cell biological, molecular biological, transplantation, genetic and transgenic methods to analyse mechanisms regulatingevents that occur during the pre- and post-natal development of cortex in various species.
We have demonstrated that the newborn cerebral cortex initially overproduces axonal connections, many of which link cortical sites that are not linked in the adult.
The mature pattern of connections emerges from this exuberant population by withdrawal of axons and death of inappropriately connected cells. We proposed that specific cortical connections develop on the basis of trial-and-error.
Axons may grow in a random fashion and may try to connect to many sites, but only those that happen to reach an appropriate target succeed in maintaining their connection.
We extended these observations through the application of quantitative methods and computer modelling, culminating in the publication of a more detailed and modified version of the original “trial-and-error” theory.
This encompassed the later observation that aspects of the development of association connections not studied in my earlier work are guided from the outset.
We have used cell and tissue culture methods to show that cortex releases growth factors that can influence and may guide the growth and survival of neurons during preand post-natal development.
Mutant mice were used to demonstrate that these growth factors include at least one member of the neurotrophin family. We have demonstrated crucial requirements for transcription factors in controlling forebrain development.
Our results demonstrate that the transcription factor, Pax6, controls cell proliferation, migration and differentiation in the embryonic neocortex, and that it regulates the growth of axons from the embryonic thalamus to the cerebral cortex.
Using genetics, transgenics, chimaeras and transplantation methods we have provided convincing evidence that the mechanisms by which Pax6 regulates these processes involves the control of molecules on the surface of forebrain cells.
Our current hypothesis is that Pax6 controls the expression of receptors that allow cells to respond correctly to signals from other cells during development.
Pratt T, Price DJ. (2016) Junk DNA Used in Cerebral Cortical Evolution. Neuron. 90:1141-3.
Mason JO, Price DJ. (2016) Building brains in a dish: Prospects for growing cerebral organoids from stem cells. Neuroscience. 334:105-118.
Borkowska M, Millar JK, Price DJ. Altered Disrupted-in-Schizophrenia-1 Function Affects the Development of Cortical Parvalbumin Interneurons by an Indirect Mechanism. PLoS One. (2016) 11:e0156082.
Caballero IM, Manuel MN, Molinek M, Quintana-Urzainqui I, Mi D, Shimogori T, Price DJ. (2014) Cell-Autonomous Repression of Shh by Transcription Factor Pax6 Regulates Diencephalic Patterning by Controlling the Central Diencephalic Organizer. Cell Rep. Aug 27.
Mi, D., Y. T. Huang, D. A. Kleinjan, J. O. Mason and D. J. Price (2013). "Identification of Genomic Regions Regulating Pax6 Expression in Embryonic Forebrain Using YAC Reporter Transgenic Mouse Lines." Plos One 8(11).
Da Mi, Catherine B. Carr, Petrina A. Georgala, Yu-Ting Huang, Martine N. Manuel, Emily Jeanes, Emi Niisato, Stephen N. Sansom, Frederick J. Livesey, Thomas Theil, Kerstin Hasenpusch-Theil, T. Ian Simpson, John O. Mason, David J. Price (2013) Pax6 exerts regional control of cortical progenitor proliferation via direct repression of Cdk6 and hypophosphorylation of Rb. Neuron; 78(2):269-84.
Nowakowski, T.J., Fotaki, V., Pollock, A., Sun, T., Pratt, T. and Price, D.J. (2013) MicroRNA-92b regulates the development of intermediate cortical progenitors in embryonic mouse brain. PNAS 110(17):7056-61.
Manuel M, Martynoga B, Yu T, West JD, Mason JO, Price DJ. (2010) The transcription factor Foxg1 regulates the competence of telencephalic cells to adopt subpallial fates in mice. Development 137:487-97.
Quinn, Jane C., Michael Molinek, John O. Mason and David J. Price. (2009) Gli3 is required cell autonomously for dorsal telencephalic cells to adopt appropriate fates during embryonic forebrain development. Developmental Biology, 327:204-15.
Simpson, Ian, Thomas Pratt, John Mason and David J Price (2009) Normal ventral telencephalic expression of Pax6 is required for normal development of thalamocortical axons in embryonic mice. Neural Development 4:19
Tian, Natasha M. M-L. Thomas Pratt, David J. Price (2008) Foxg1 regulates retinal axon pathfinding by repressing an ipsilateral program in nasal retina and causing optic chiasm cells to exert a net axonal growth-promoting activity. Development, 135:4081-9.
Manuel M, Georgala PA, Carr CB, Chanas S, Kleinjan DJ, Martynoga B, Mason JO, Molinek M, Pinson J, Pratt T, Quinn JC, Simpson TI, Tyas DA, van Heyningen V, West JD and Price DJ (2007) Controlled overexpression of Pax6 in vivo negatively autoregulates the Pax6 locus, causing cell-autonomous defects of late cortical-progenitor proliferation with little effect on cortical arealization. Development 134:545-55.