A long-standing and central effort of our laboratory has been the generation of genetically engineered mouse models (GEMMs) to study human disease. One major line of research is to study cancers of the nervous system and the genetic disease, Von Recklinghausen's Neurofibromatosis type 1 (NF-1), which is caused by mutation of a tumor suppressor. Our various strains of Nf1 null mice have become important tools for studying the NF-1 disease as it relates to malignancy. Using Nf1 conditional knockouts, we are now investigating its role in the development of dermal and plexiform neurofibromas and malignant peripheral nerve sheath tumors, as well as its role in Schwann cell development, and in learning disabilities. Additionally, mice with mutations in Nf1, p53, and Pten develop brain tumors with 100% penetrance that molecularly and histologically resemble human glioma, and we have shown that these tumors arise from neural stem/progenitor cells that reside within the subventricular zone, a neurogenic niche of the brain. In addition to functional characterization of the mutant mice at the cellular and molecular levels, we have added characterization of inhibitory small compounds to our repertoire. These were derived from high-throughput chemical compound screens designed to identify molecules that inhibit growth of these cells. These physiologically relevant mouse models of human glioma and NF1 are powerful tools for investigating the initiation and progression of tumors associated with these devastating diseases and provide a useful biological system for testing possible therapies.
Another area of investigation concerns the functions of the Trk gene family, which encodes transmembrane receptor tyrosine kinases (RTKs) that act as functional receptors for the nerve growth factor (NGF) family of neurotrophin ligands. In the past we have made gene targeted knockout mutations in mice by homologous recombination for the genes encoding the neurotrophins: brain derived neurotrophic factor (BDNF), neurotrophin-3 (NT3), neurotrophin 4/5 (NT4/5), as well as for the TrkA and TrkB receptors. These studies have allowed us to reveal the essential nature of the neurotrophin ligands, their receptors, and their downstream signaling pathways in the survival of early neurons in addition to more complex phenotypes in the central and peripheral nervous systems. More recent application of conditional knockout technology makes it possible to mutate the Trk family and neurotrophin family genes in specific tissues or cell types. This approach allows more precise analysis of neurotrophin function in the CNS where evidence points to a role in development, synaptic plasticity and behavior. These mouse models have also proved useful for studying aspects of neuropsychiatric disorders, including depression, and we are currently investigating the role of hippocampal neurogenesis in anti-depressant response. These studies have also been extended to the study of signaling molecules downstream of Trk receptors and with this approach, novel models of autism have been developed and are under study. Finally, this work has served as a useful entry point for the study of adult neural stem cell biology in the hippocampus and subventricular zone.