Jacquelyn Bond

The role of human ASPM in neurogenesis

Determining how the human brain develops and functions is arguably 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 leading to reduced brain size and mental retardation.

MCPH is a heterogeneous disease, caused by mutation in any of at least six genes, but resulting in one clinically virtually indistinguishable disease. Mutation in the abnormal spindle-like microcephaly associated gene (ASPM) at the MCPH5 locus accounts for over half of the MCPH cases in the Northern Pakistani population. The human ASPM gene encodes a 3477 amino acid protein which is predicted to contain an amino terminal microtubule binding domain, at least one calponin homology domain, up to 81 predicted calmodulin binding isoleucine-glutamine (IQ) motifs, a single armadillo region and a carboxyl-terminal region of unknown function. Mutations are spread throughout the gene and are believed to cause premature protein truncation or nonsense-mediated decay. During neurogenic development, murine Aspm is expressed in the neuroepithelium of the lateral ventricles of the developing brain. ASPM localizes to the poles of the mitotic spindle during mitosis. We are currently performing functional studies of ASPM in order to increase our understanding of neurogenesis and of the MCPH disease pathway.

Bond J, Woods CG (2006) Cytoskeletal genes regulating brain size. Curr Opin Cell Biol 18:95-101.

Woods CG, Bond J, Enard W (2005) Autosomal recessive primary microcephaly (MCPH): a review of clinical, molecular, and evolutionary findings. Am J Hum Genet 76:717-28.

Bond J, Roberts E, Springell K, Lizarraga SB, Scott S, Higgins J, Hampshire DJ, Morrison EE, Leal GF, Silva EO, Costa SM, Baralle D, Raponi M, Karbani G, Rashid Y, Jafri H, Bennett C, Corry P, Walsh CA, Woods CG (2005) A centrosomal mechanism involving CDK5RAP2 and CENPJ controls brain size. Nat Genet 37:353-5.

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 (2003) Protein-truncating mutations in ASPM cause variable reduction in brain size. Am J Hum Genet 73:1170-7.

Bond J, Roberts E, Mochida GH, Hampshire DJ, Scott S, Askham JM, Springell K, Mahadevan M, Crow YJ, Markham AF, Walsh CA, Woods CG (2002) ASPM is a major determinant of cerebral cortical size. Nat Genet 32:316-20.