Our long-standing interest lies in the elucidation of intracellular regulatory pathways that control the complex process of vertebrate development. To this end, we initially studied the developmental expression of various proto-oncogenes in a search for clues that might give insight into regulatory developmental pathways. Through the discovery of proto-oncogenes that exhibit interesting patterns of expression, in the late eighties we began to pursue functional studies to elucidate essential roles in regulation of embryonic development and, in turn, investigate their roles in cancer using mouse models.
A central effort has focused on the modeling of human disease including autism, brain cancer, and Von Recklinghausen's Neurofibromatosis type 1 (NF-1), which is caused by mutation of a tumor suppressor. Our studies of the NF-1 gene have led to the discovery that its protein product, neurofibromin, is a negative regulator of signaling mediated by the Trk receptor tyrosine kinase (RTK). We have generated Nf1 null mice that have become an important model for the NF-1 disease as it relates to malignancy. Through more recent generation of conditional knockouts of Nf1, we are presently studying its role in dermal and plexiform neurofibroma development, Schwann cell development, and learning disabilities. Additionally, mice with mutations in Nf1, p53, and Pten develop brain tumors with 100% penetrance that molecularly and histologically resemble human glioma. Using genetic and stereotactic injection methods, we have shown that these tumors arise from neural stem/progenitor cells that reside within the subventricular zone, a neurogenic niche of the brain. 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 line of study 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 and their receptors 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.