Effects of Von Hippel-Lindau (VHL) gene deficiency on the human central nervous system

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer disorder caused by a germline mutation in the VHL tumor suppressor gene. Loss of the wild-type allele results in VHL deficiency and subsequent tumor formation. One common tumor in VHL patients is the cerebellar hemangioblastoma of which the histogenesis is unknown. Multiple, microscopic, VHL-deficient precursors, termed developmentally arrested structures (DASEs), were recently identified in spinal nerve roots of the peripheral nervous system. These DASEs can proliferate and differentiate, growing into the spinal cord to form frank tumor. Therefore, the hypothesis that DASEs exist in the central nervous system proper was tested. The cerebella from five VHL autopsy patients were systematically sampled. Ten DASEs in toto were found from microscopic examination of 385 tissue samples. Similar to nerve root DASEs, the cerebellar DASEs were composed of poorly differentiated cells that expressed HIF2α and CAIX, consistent with VHL deficiency, and abundant capillaries. Analogous to nerve root, all ten DASEs involved the molecular layer, indicating the tumor site of origin. Because VHL cerebellar tumorigenesis resembles hemangioblast development in the embryo, the hypothesis that the tumor cell of origin is a developmentally arrested hemangioblast was tested. Immunohistochemistry experiments on cerebellar DASEs with the antibody brachyury, a mesodermal marker expressed in both hemangioblasts and hemangioblastomas, showed no immunoreactivity. The hypotheses that the tumor cell of origin is a granule or basket/stellate cell progenitor, both of which occupy the molecular layer during development, were also tested. Cerebellar DASEs and tumors did not immunoreact with the antibody ZIC1, a granule cell progenitor marker. Rather, cerebellar DASEs and tumors immunoreacted with the antibody PAX2, a marker for basket/stellate cell progenitors. Furthermore, VHL cerebellum expressed PAX2 in cells located between Purkinje cell somata and in the contiguous molecular layer, resembling histological and molecular development of basket/stellate cells in the postnatal mouse and human cerebellum. It is proposed that an early effect of VHL gene deficiency in human cerebellum is developmental arrest of basket/stellate cells in the Purkinje and molecular layers at a young, postnatal age. These PAX2-positive, initiated cells await another insult to form DASEs and eventually, tumors