Tiny and seemingly simple organelles can cause big problems for an organism, if they get out of control. The centrosome, composed of just two barrel-shaped centrioles and a mass of proteins in human cells, forms the microtubule organizing center that regulates cell division (cytokinesis). During cell division, two centrosomes at opposite poles of the cell work together to position the mitotic spindle. An increase in the number of centrosomes is "a hallmark of human tumors," according to VĂ©ronique Marthiens and Renata Basto at the Curie Institute in Paris who report in Nature Cell Biology on their surprising results in mice after adding extra centrosomes in the cells of the developing central nervous system (CNS).The genetically engineered mice died shortly after birth but the researchers found no brain tumors in the mice. Instead, the mice had microcephaly: a neurodevelopmental disorder characterized by small head and brain. Although centrosome- and spindle-associated genes have been implicated in microcephaly, this is the first time an increase in centrosome number has been correlated with decreased brain size.
"This is the story of every cell biological defect that causes disease," said Tom Misteli, Senior Investigator at NIH, in singling out the paper for the ASCB Post. "How what might seem like a minor defect in a subcellular process (a few centrosomes too many) is amplified by cellular behavior (failure of neuronal stem cells to divide properly) and can lead to dramatic disease symptoms (microcephaly)."
Until now, microcephaly was thought to result from defects in the position of the mitotic spindle, which would lead to defective cell division and depleted reserves of CNS stem cells. Marthiens and colleagues did not find changes in spindle positioning in their microcephalic mice, though they did observe abnormal cell divisions and changes in chromosome number (aneuploidy). Consistent with previous reports in microcephalic mice, they also observed an increase in programmed cell death (apoptosis) in the microcephalic brains. Together, these effects suggest that microcephaly can result from increased centrosome number, which results in abnormal cell division.