Investigating the function of human ASPM in neurogenesis
Determining how the human brain develops and functions is one of the greatest questions facing scientists today. To gain an insight into this process we are studying the disorder autosomal recessive primary microcephaly (MCPH). MCPH is a disease of early neuronal development characterized by reduced brain size and associated mental retardation (OMIM 251200 http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim). MCPH is a heterogeneous disease, but results in virtually one clinically indistinguishable disease. This syndrome is a unique research model in which to study the regulation of early neurogenesis.
Mutations in the abnormal spindle-like microcephaly associated gene (ASPM) at the MCPH5 loci, are the most common cause of MCPH. ASPM encodes a 3477 amino acid protein, which is predicted to contain a microtubule-binding domain, two calponin homology domains, up to 81 isoleucine-glutamine (IQ) motifs, a single armadillo region and an NH2 region of unknown function. During neurogenic development murine Aspm is expressed in the neuroepithelium of the brain. ASPM is nuclear in interphase, but localizes to the spindle poles during mitosis.
We currently investigate the function of human ASPM and its role in neurogenesis and have established many unique ASPM resources. Our most recent research highlights are the identification of a number of exciting ASPM interacting proteins, including known regulators of mitosis and demonstrating that ASPM has roles in cytokinesis and spindle orientation through siRNA mediated ASPM depletion experiments. These processes are crucial in controlling the ratio of neuronal progenitor cell proliferative to neurogenic mitosis in early neurogenesis. To increase our understanding of neurogenesis and the MCPH disease pathway we are currently performing functional studies of ASPM.
In collaboration with Dr Sandra Bell and Dr Ewan Morrison our second research focus is determining the expression profiles of specific mitotic proteins during cancer development with the intension of identifying cancer biomarkers and developing novel cancer therapies.
Dr Jacquelyn Bond - Group Leader, Senior Lecturer
Mrs Basma AlEnezy - PhD student
Brüning-Richardson A, Bond J, Alsiary R, Richardson J, Cairns DA, McCormack L, Hutson R, Burns P, Wilkinson N, Hall GD, Morrison EE and Bell SM. ASPM and microcephalin expression in epithelial ovarian cancer correlates with tumour grade and survival. Br. J. Cancer 2011 104:1602-10.
Higgins J, Midgley C, Bergh A-M, Bell SM, Askham JM, Roberts E, Sharif SM, Bennett C, Glover DM, Woods CG, Morrison EE, Bond J. Human ASPM participates in spindle organisation, cleavage furrow orientation and cytokinesis. BMC Cell Biology 2010 11:85.
Bond J, Roberts R, Springell K, Lizarraga S, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SMR, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG. A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat. Genet., 2005 37:353-355.
Bond J , Scott S, Hampshire DJ, Springell K, Corry P, Abramowicz MJ, Mochida GH, Hennekam RC, Maher ER, Fryns JP, Alswaid A, Jafri H, Rashid Y, Mubaidin A, Walsh CA, Roberts E, Woods CG. Protein-Truncating Mutations in ASPM Cause Variable Reduction in Brain Size. Am. J. Hum. Genet., 2003 73:1170-1177.
Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA and Woods CG. ASPM is a major determinant of cerebral cortical size. Nat. Genet., 2002 32:316-320.
BioMedical and Health Research Centre (Leeds) Technology platform funding. Co Applicant. Establish a technology platform to perform high content high throughput whole and part-genome siRNA libraries and to develop non-antibody binding reagents. October 2010 November 2014.
Yorkshire Cancer Research. Project grant, Co-applicant. siRNA screen to identify modifiers of MCPH1 induced premature chromosome condensation. March 2011-February 2014.
BioMedical and Health Research Centre (Leeds). Lead applicant. Pump priming funding. Identification of mitotic genes involved in premature chromosome condensation, centrosome and microtubule function by genome wide siRNA screening. January 2013- January 2014.
Self-funded students are always welcomed to apply for postgraduate study. International students must meet the entry requirements for English. Bench fees are required.
Please email J.Bond@leeds.ac.uk for informal enquiries.