Sequence of cellular events in cerebellar ontogeny relevant to expression of neuronal abnormalities in ataxia-telangiectasia.

An attempt was made to relate expression of neuronal abnormalities in ataxia-telangiectasia (AT) to the sequence of normal cellular events in the developing human cerebellum. Previous light and electron microscopic analyses indicate that the cerebellar cortex in humans develops during a protracted period that spans 8 fetal and 12 postnatal months. However, the Purkinje cells that comprise the most obvious lesion in the AT disorder are all generated before the end of the fourth fetal month. Correlative Golgi studies in human and [3H]thymidine labeling of DNA in dividing cerebellar cells in rhesus monkey demonstrate that after the last mitotic division Purkinje cells migrate to the cortical plate where they form a well-defined stratum below the embryonic molecular layer. Only thereafter do they begin to differentiate and develop their large dendritic tree. The dendrites grow in coordination and simultaneously with the genesis of parallel fibers in the molecular layer. The parallel fibers--the horizontal portion of granule cell axons--form between the fourth fetal and twelfth postnatal month in a well-defined inside-outside order, the earliest generated fibers being situated near the Purkinje cell layer and the last fibers generated lying closer to the pial surface. The four cases of AT examined in this study showed the usual neuropathological changes, which include a variable degree of Purkinje and granule cell loss. However, we emphasize here an abnormality of dendritic arborization and the presence of displaced Purkinje cells, which are situated in the middle and superficial strata of the molecular layer. Based on the sequence of histogenetic events, we argue that neither abnormal arborization nor aberrant position could be attained after parallel fibers of the deeper strata have been laid down and after Purkinje cells have formed their dendritic tree. Therefore, we suggest that the AT disorder in these cases must affect Purkinje cell differentiation or the interaction of these cells with parallel fibers during the first half of gestation, which is considerably earlier than any other recognized expression of the disorder. The subsequent degeneration of Purkinje cells is apparently not related to the aberrant position of the somas, since many Purkinje cells situated in normal position also die and there is no evidence that displaced cells degenerate at a slower or more rapid rate. The early expression of AT in the central nervous system provides new insight into possible pathogenesis and opens new avenues for research.