An embryonic origin for medulloblastoma.

Medulloblastoma is a common brain tumor of children. Three differentiated cell types are found in medulloblastomas: neurons, glia, and muscle cells. Because of the presence of multiple differentiated cell types these tumors were named after a postulated cerebellar stem cell, the medulloblast, that would give rise to the differentiated cells found in the tumors. We describe a cell line with the properties expected of the postulated medulloblast. The rat cerebellar cell line ST15A expresses an intermediate filament, nestin, that is characteristic of neuroepithelial stem cells. ST15A cells can differentiate, gaining either neuronal or glial properties. In this paper we show that the same clonal cell can also differentiate into muscle cells. This result suggests that a single neuroectodermal cell can give rise to the different cell types found in medulloblastoma. We also show expression of nestin in human medulloblastoma tissue and in a medulloblastoma-derived cell line. Both the properties of the ST15A cell line and the expression of nestin in medulloblastoma support a neuroectodermal stem cell origin for this childhood tumor.

Downregulation of CDC2 upon terminal differentiation of neurons.

The terminal differentiation of neurons occurs as precisely timed waves, with specific neuronal types differentiating in defined sequences. The precision of neuronal differentiation in the central nervous system offers an unusual opportunity to study terminal differentiation in vivo. The p34cdc2 kinase complex and the anti-oncogenes p53 and RB are central in the regulatory network that controls cell proliferation. We found high levels of expression of CDC2 mRNA and protein in proliferating neuronal precursor cells. The expression of both CDC2 and cyclin A was dramatically downregulated upon terminal differentiation of neurons in vivo and in a neuronal precursor cell line, ST15A. p53 mRNA expression was also downregulated but to a lesser extent; RB mRNA levels were unchanged during neuronal differentiation. Immunohistochemistry showed that p34cdc2 was expressed not only in the neuronal precursors of the cerebellar external granule layer but also in the early differentiating granule neurons. The expression of p34cdc2 in early neurons suggests a function for this enzyme in the events that occur soon after proliferation ceases. On the basis of the results reported here and other recent findings, we propose a model in which terminal differentiation is achieved by a switch in the neuronal precursors from p34cdc2-based proliferation to a differentiated state controlled by p34cdc2-related kinases.