Molecular Basis of Normal and Neoplastic Proliferation in the Nervous System

Dr. Wetmore is a new recruit to Mayo and is an assistant professor in the Division of Pediatric Hematology/Oncology, with joint appointments in Neurology and Biochemistry and Molecular Biology. Dr. Wetmore?s research program is focused on elucidating the molecular and genetic basis of cell proliferation in the nervous system as it underlies normal development and tumorigenesis. Her laboratory utilizes mouse models as well as cell culture to investigate signaling pathways involved in proliferation of neuronal precursors.

Unlike brain tumors that arise in the adult population, which are largely supratentorial and of glial origin, pediatric brain tumors most often occur in the hind part of the brain and arise from cells of neuronal lineage. A variety of studies have demonstrated that granule cell proliferation and differentiation are dependent upon genetic as well as environmental factors produced by neighboring cells in the cerebellum.

Progress in understanding the etiology of pediatric brain tumors has been hampered by the lack of an appropriate animal model. It has been reported that subsets of sporadic and some hereditary medulloblastomas contain mutations in a developmental signaling pathway involving mammalian homologues of the Drosophila (fruit fly) segment polarity gene, patched (ptc) and its ligand, sonic hedgehog (shh). Dr. Wetmore?s work has demonstrated that heterozygous disruption of patched (Ptc) in mice results in the spontaneous development of posterior fossa tumors that closely resemble medulloblastoma. However, only 14% of mice heterozygous for Ptc develop medulloblastoma over a period of 10 months indicating that it is likely that additional genetic lesions are required for oncogenic transformation. Of note, however, is that the normal Ptc allele continues to be expressed in these tumors, indicating that additional genetic lesions are required for oncogenic transformation.

Ongoing experimental studies:

The aim of our present research is to investigate the possible involvement of tumor suppressor genes in medulloblastoma and to investigate other genes that may contribute to the proliferation and differentiation of cells in the nervous system. Investigation into the molecular basis of medulloblastoma may give insight to the genetic regulation of the normal proliferative capacity of cells in the central nervous system. We are also interested in the signaling pathways that drive cellular self-renewal (neural stem cells) in the nervous system and in asking whether tumors exploit similar pathways to maintain their proliferative state. Understanding more about the genetic control of neural stem cell proliferation may also provide insight to the genetic changes that direct a presumptively post-mitotic neuronal cell to re-enter or persist in the cell cycle to form a tumor. By understanding the mechanisms that drive the proliferation of cells during normal nervous system development as well as in disease we will be better able to develop therapeutic agents that specifically inhibit tumor growth.