Molecular Neurogenetics Unit
Lee B. Jacoby, PhD

Molecular Neurogenetics Unit CV  |  Recent Publications | Links

Molecular Neurogenetics Unit CNY 149-6223 Telephone: 617-724-1730 Fax: 617-726-5736 Email: jacoby@helix.mgh.harvard.edu Jacoby Publications Jacoby Pubs 2001 Jacoby Pubs 2000 Jacoby Pubs 1999

The long-term goal of our research is to understand the molecular genetic basis of nervous system tumors, particularly those associated with neurofibromatosis (NF) types 1 and 2, including neurofibromas and neurofibrosarcomas in NF1 and schwannomas, meningiomas and ependymomas in NF2. Both the NF1 and NF2 genes have been isolated, and both appear to be tumor suppressor genes, whose loss of function is associated with tumor formation. Currently we are analyzing mutations in the NF2 gene in schwannomas and other NF2-associated tumors. Most of these mutations result in frameshifts, creation of stop codons, or interference with normal splicing of the NF2 transcript and are predicted to cause truncated proteins. However, in-frame deletions and missense mutations have also been found, and these may pinpoint particular domains of the protein that are critical for its normal function, and, when disrupted, lead to tumor formation. In many cases two different mutations have been found in the same tumor, providing strong support for the tumor suppressor model in which both copies of the gene must be inactivated for the cell to escape normal growth control and form a tumor.

The NF2 gene product, called merlin, is a member of a highly conserved family of proteins that link cytoskeletal components with the cell membrane. We are examining the effects of alterations in the NF2 gene on its transcript. Several NF2 mutations have been shown to cause aberrant splicing of the NF2 transcript, and currently we are determining if these mutations or others also affect the amount of NF2 mRNA expressed. We are also examining the expression of the NF2 gene in normal human Schwann cells and in cells cultured from schwannomas. The effects of antisense oligonucleotides or antisense NF2 mRNA on Schwann cell morphology, growth and ability to differentiate are being determined. Finally, we are characterizing the expression of neuregulins, a large family of transmembrane polypeptide growth factors, in normal Schwann cells and Schwann cell tumors, to determine if abnormal expression of neuregulins or their receptors is important in the proliferation of Schwann cells in neurofibromatosis. These investigations should increase our understanding of how defects at the NF1 or NF2 loci lead to the formation of both familial and sporadic nervous system tumors, and they should lay the foundation for developing effective therapies for preventing the formation of tumors or slowing the growth of tumors associated with neurofibromatosis.

Neurosurgery Clinical Units MGH Neurosurgical Service Spine Tumor Center at MGH Brain Tumor Center at MGH Research at MGH Neurosurgery Neuroscience Care Units at MGH Residents at Neurosurgery