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Exploring the mitotic functions of ASPM in human brain size regulation


Project Description

The increase in relative brain size is one of the most striking events in human evolution. To determine how human brain size is normally regulated we have investigated the cause of autosomal recessive primary microcephaly (MCPH), a congenital disorder of reduced brain size and associated mental retardation. MCPH is a disorder of reduced neural progenitor cell and neuronal cell number in the developing brain.

Homozygous mutations in the Abnormal Spindle-Microtubule Assembly gene (ASPM – previously named Abnormal Spindle -like Microcephaly associated gene) are the most common cause of MCPH1. ASPM is a 410kDa microtubule associated protein which localises to the spindle poles during mitosis and to the midbody during cytokinesis2-3. Analysis of patient cells containing ASPM mutations and cell lines in which ASPM has been reduced using siRNA have identified a number of mitotic functions for ASPM. Notably, interactions involving the C-terminus of ASPM are involved in the final stages of cytokinesis. We wish to further investigate the protein pathways involved in this.

Using cell-based siRNA library screening, Yeast-two hybrid and other interaction studies, we have identified a number of ASPM interacting proteins that we hypothesize to be involved in spindle orientation, cytokinesis, cytoskeletal organisation, structural changes in ASPM and the regulation of ASPM activity. This PhD project will validate and further study a number of these protein interactions.

The project will utilise a range of biochemical, molecular biological and cell biological techniques. Gain or loss-of-function cellular phenotypes will be assessed by over-expression and siRNA-mediated knockdown of gene expression in cultured cells, alongside analysis in a unique resource of MCPH patient primary cells. Live cell imaging, confocal microscopy, super resolution microscopy and high throughput imaging will complement these approaches. The programme of work will provide a motivated and enthusiastic post-graduate researcher with an excellent foundation in research training in a range of modern techniques including PCR, cloning, co-immunprecipitation, GST fusion pull down assays, siRNA gene knockdown, cell culture, RNA extraction, Real time PCR, immunofluorescence staining, Western blotting and cellular imaging of fixed and live cells.

Eligibility
You should hold a strong first degree equivalent to at least a UK upper second class honours degree in a relevant subject area.

The Faculty minimum requirements for candidates whose first language is not English are:

• British Council IELTS - score of 6.5 overall, with no element less than 6.0
• TOEFL iBT - overall score of 92 with the listening and reading element no less than 21, writing element no less than 22 and the speaking element no less than 23.

How to Apply
To apply for this scholarship applicants should complete a Faculty Scholarship Application form using the link below https://medicinehealth.leeds.ac.uk/downloads/download/129/faculty_graduate_school_-_application_form and send this alongside a full academic CV, degree certificates and transcripts (or marks so far if still studying) to the Faculty Graduate School

We also require 2 academic references to support your application. Please ask your referees to send these references on your behalf, directly to

If you have already applied for other scholarships using the Faculty Scholarship Application form this academic year you do not need to complete this form again. Instead you should email to inform us you would like to be considered for this scholarship project.

Any queries regarding the application process should be directed to

Funding Notes

This project is available for self funding applicants only.

References

1. Bond et al., 2003, Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Human Genet. 73:1170-1177
2. Bond et al., ASPM is a major determinant of cerebral cortical size. 2002, Nat Genet. 32:316-20
3. Higgins et al., Human ASPM participants in spindle organisation, spindle orientation and cytokinesis. 2010 BMC Cell Biol. 11:85-101

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