Abstract
A several lines of evidence such as animal experiments and epidemiological studies of A-bomb survivors indicated that radiation exposure in utero of the embryo or fetus induces growth retardation and microcephaly with mental retardation. However, the molecular and cellular mechanism of radiation-induced microcephaly remains unclear. We try to dissect the molecular pathology of human genetic microcephaly in order to understand the essential mechanism of radiation-induced microcephaly.
Seckel syndrome is an autosomal recessive and genetic heterogeneous disorder of severe microcephaly and short stature. So far, the ATR gene and centrosomal Pericentrin/ PCNT gene were identified as the responsible genes for Seckel syndrome. Here, we identified the mutations of the PCNT gene in two Japanese Seckel syndrome patients, and found that PCNT regulated cell cycle at some checkpoints. Mitotic index after UV treatment was significantly increased in PCNT-Seckel syndrome cells as compared with wild-type cells. In contrast, PCNT-Seckel syndrome did not exhibit radiation sensitivity. These results suggest that PCNT is a component of ATR signaling pathway and controls the G2/M checkpoint. Next, we found that the population of cells with primary cilia, a hair-like cell surface structure at G0/G1 phase, was significantly increased in PCNT-Seckel primary skin fibroblasts, and that the patient cells inhibited BrdU uptake despite of the presence of proliferation marker Ki-67. Taken together, we conclude that PCNT-Seckel Syndrome cells fall into G1 phase arrest. The control mechanism of G1/S phase transition by PCNT is currently under investigation.
