Section of Ophthalmology and Neuroscience

Jacquelyn Bond

MICROCEPHALY AND NEUROGENESIS RESEARCH GROUP

Wellcome Trust Research Career Development Fellow

j.bond@leeds.ac.uk

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 congenital disorder autosomal recessive primary Microcephaly (MCPH), a disease of early neuronal development characterized by reduced brain size and mental retardation. MCPH is a heterogeneous disease, but results in virtually one clinically indistinguishable disease. The most common cause of MCPH is mutation in the abnormal spindle-like microcephaly associated gene (ASPM). Pathogenic mutations are spread throughout ASPM and cause premature protein truncation or nonsense mediated decay. 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. During mitosis ASPM localizes to the mitotic spindle poles. We hypothesize MCPH is a disorder of neurogenic mitosis, resulting in a reduction of cell number in the developing human brain. To increase our understanding of neurogenesis and the MCPH disease pathway we are currently performing functional studies of ASPM.

Figure 1 Predicted ASPM domain structure; microtubule binding domain (grey box), calponin homology region (white box), IQ domains (filled bars), armadillo repeat (blue box) and a terminal region (diagonal striped box). Arrows indicate protein truncating mutations and dashed line depicts translocation breakpoint.

Figure 2 Immunofluorescence image of the mitotic localization of ASPM, showing the DNA metaphase bar (blue), α-tubulin of the mitotic spindle (red) and ASPM at the spindle poles (green)