Past Research
During my research career I was interested in the control of gene expression during the early stages of development in vertebrates, especially transcriptional regulation (both genetic and epigenetic) with respect to nervous system development. In addition I was interested in the role of genetic and epigenetic regulation in the formation of cancer, focussed on germ cell tumours and brain tumours .
Specific Areas of Research:
The role and mechanism of Sox transcription factors in early zebrafish development
The nervous system arises from the early embryonic ectoderm via a choice between neural (prospective CNS) and non-neural (prospective epidermal) fates. We are use the zebrafish to dissect the molecular signaling events that underlie this choice. These studies are focused on the mechanisms by which extracellular signals results in transcriptional changes in recipient cells. Sox transcription factors play a central role in these responses. Our work focuses on the role of the Sox factors in the formation of both the central nervous system and the earlier organizer tissue from which neural inducing signals eminate. In particular we are studying how Sox3 can repress some genes while activating others.
Sox2 function in neural stem cells
Once the nervous system is established, its growth is sustained by dividing cells known as 'neural stem cells'. A small number of these cells survive into adulthood and are the centre of an intense research effort to develop prospective therapeutic strategies for neurodegenerative diseases. We are studying the mechanism of action of Sox2 in regulating the behaviour of neural stem cells.
Role of the transcription factor, CIC, in brain tumours
Many years ago we identified an unusual transcription factor called CIC (derived from the Drosophila gene name, capicua). In recent years this genes has been implicated in a neurodegenerative disorder, spinocerebellar ataxia) and in the brain tumour oligodendrocytoma. We have therefore recently begun to analyse this gene in more detail. In collaboration with Dr Stephan Pusch, we are investigating how CIC performs its biochemical activities in order to fully understand why specific mutations lead to the initiation of oligodendrocytomas.
DNA methylation in Germ Cell Tumours
We have a particular interest in a second group of brain tumours in children, the cranial germ cell tumours. These are very rare, so we have gone on to include adult germ cell tumours in out studies. Our interest here is in the role of DNA methylation in these tumours. germ cell tumours are made up of a diverse range of tumour types. Seminomatous tumours resemble germ cell progenitors, are homogenous and, while being malignant, are highly curable due to their extreme sensitivity to chemotherapy. Yolk sac tumours by contrast exhibit complex cellular morphology and are less chemosensitive. These two type of germ cell tumour have very different levels of genomic methylation. We are investigating how this is linked to their general biology and to their chemosensitivity
Sox genes in neural stem cells
Once the nervous system is established, its growth is sustained by dividing cells known as 'neural stem cells'. A small number of these cells survive into adulthood and are the centre of an intense research effort to develop prospective therapeutic strategies for neurodegenerative diseases. We have studied the expression and function of the Sox family of transcription factors in regulating the behaviour of neural stem cells for many years.
Paediatric Brain Tumours
Brain tumours are the most common solid tumours in young children. The cure and treatment of these tumours has advanced poorly in comparison to other classes of tumour. Previously, we have studied the expression of embryonic regulatory factors in brain tumour tissue. We then set out to elucidate the molecular mechanisms controlling the initiation of these tumours. In particular we investigated the role of epigenetic alterations in triggering tumour formation from neural stem cells (Funded by Ali¹s Dream, Charlie¹s Challenge and The Children¹s Brain Tumour Research Centre). We also have a particular interest in a second group of brain tumours in children, the cranial germ cell tumours. We have studied the cellular origins and molecular mechanisms by which these tumours arise (Funded by the Samantha Dickson brain Tumour Trust and AICR). In particular we have investigated the role of Oct4 in these tumours.
This work was funded by The Children's Brain Tumour Research Centre and the Samantha Dickson Research Trust , Ali's Dream and Charlie's Challenge.
Other Projects:
We have also collaborated with Professor Sadao Yasugi's group at the Tokyo Metropolitan University in Japan. Together, we have analysed the role of Sox genes in gut endoderm development. We have ongoing collaborations with others in Nottingham in the areas of Muscular Dystrophy and cancer
References:
CLAPP, J., MITCHELL, L.M., BOLLAND, D.J., FANTES, J., CORCORAN, A.E., SCOTTING, P.J., ARMOUR, J.A.L. and HEWITT. J.E., 2007. Evolutionary conservation of a coding function for D4Z4, the tandem DNA repeat mutated in facioscapulohumeral muscular dystrophy. American Journal of Human Genetics, 81(2), 264-279.
EL-ZAATARI, M, TOBIAS, A, GRABOWSKA, AM, KUMARI,R, SCOTTING,PJ, KAYE, P, ATHERTON, J, CLARKE, PA, POWE, DG AND WATSON, SA 2007. De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis. British Journal of Cancer.
ISHII, Y, REX, M, SCOTTING, PJ AND YASUGI, S (1998) Region specific expression of Chicken Sox2 in the developing gut and lung epithelium: regulation by epithelial-mesenchymal interactions. Dev Dynamics 213: 464-475
SAKAMOTO, N, FUKUDA, K, WATANUKI, K, KOMANO, T, SCOTTING, PJ AND YASUGI, S(2000) Role for cGATA-5 and cSox2 in transcriptional regulation of embryonic chicken pepsinogen gene by epithelial-mesenchymal interaction in developing chicken stomach. Developmental Biology 223, 103-113
MATSUSHITA, S., ISHII, Y., SCOTTING, P. J., KUROIWA, A. and YASUGI, S., 2002. Pre-Gut Endoderm of Chick Embryos Is Regionalized by 1.5 Days of Development. Developmental Dynamics, 223(1), 33-47.