Abstract
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.
Highlights
Within the central nervous system, production of the correct number of neurons from a pool of progenitor cells requires tight regulation of neural proliferation
We investigated the neurodevelopmental effects of morpholino-mediated knockdown of stil, aspm, wdr62 and odf2 in the developing zebrafish retina
We have demonstrated that the MCPH gene homologues stil, aspm and wdr62 are essential for normal progenitor proliferation in the developing zebrafish retinal neuroepithelium
Summary
Within the central nervous system, production of the correct number of neurons from a pool of progenitor cells requires tight regulation of neural proliferation. The genes associated with autosomal recessive primary microcephaly (MCPH) are thought to be key regulators of this process. MCPH is characterized by a significant reduction in brain volume (greater than 3 standard deviations below the mean for age and sex) associated with mental retardation [1]. License http://creativecommons.org/licenses/by/3.0/, which permits unrestricted use, provided the original author and source are credited. MCPH is a rare autosomal recessive condition and is genetically heterogeneous. Since 2002, nine different causative genes have been identified: microcephalin [3], aspm [4,5,6], stil [7], cdk5rap2/cep215 [8], cenpj/cpap [8,9,10], cep152 [11,12], cep63 [13], cep135 [14] and wdr62 [15,16,17,18,19]
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