Novorol, C., Burkhardt, J., Wood, K.J., Iqbal, A., Roque, C., Coutts, N., Almeida, A.D., He, J., Wilkinson, C.J., and Harris, W.A. (2013) Microcephaly models in the developing zebrafish retinal neuroepithelium point to an underlying defect in metaphase progression. Open Biology. 3(10):130065.
Autosomal recessive primary microcephaly (MCPH) is a congenital disorder characterized by significantly reduced brain size
and mental retardation. Nine genes are currently known to be associated with the condition, all of which encode centrosomal
or spindle pole proteins. MCPH is associated with a reduction in proliferation of neural progenitors during fetal development.
The cellular mechanisms underlying the proliferation defect, however, are not fully understood. The zebrafish retinal neuroepithelium
provides an ideal system to investigate this question. Mutant or morpholino-mediated knockdown of three known MCPH genes (stil, aspm and wdr62) and a fourth centrosomal gene, odf2, which is linked to several MCPH proteins, results in a marked reduction in head and eye size. Imaging studies reveal a dramatic
rise in the fraction of proliferating cells in mitosis in all cases, and time-lapse microscopy points to a failure of progression
through prometaphase. There was also increased apoptosis in all the MCPH models but this appears to be secondary to the mitotic
defect as we frequently saw mitotically arrested cells disappear, and knocking down p53 apoptosis did not rescue the mitotic
phenotype, either in whole retinas or clones.