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Faculty List
David Anderson
mancusog@caltech.edu
Ph.D., 1983, Rockefeller University
Growth and Transcription Factors Controlling Mammalian Neural Stem Cell Development
There are currently three major areas of investigation in this laboratory: the development of the nervous system; the development of the circulatory system; and the functional neuroanatomy of fear.
Our studies of neural development focus on the control of differentiation in the vertebrate peripheral nervous system, which derives from the neural crest. We have isolated and characterized stem-like progenitor cells exhibiting multipotency and self-renewal capacity, and are investigating the control of the fate of these cells by both cell-extrinsic and cell-intrinsic factors. Our experimental approaches include in vitro clonal analysis, in vivo transplantation, and loss- and gain-of-function genetic manipulations in mouse and chick embryos. Subtractive hybridization and microarray analysis are being used to identify genes that distinguish stem and progenitor cells at various stages of development. We are also investigating the molecular basis of the specification of sensory neuron identity, connectivity and function.
Our studies of the circulatory system stem from our serendipitous discovery that arteries and veins are genetically distinct from the earliest stages of angiogenesis. Arteries express the transmembrane ligand ephrinB2, and veins express one of its receptors, EphB4. Gene-targeting studies have indicated that reciprocal ephrinB2-EphB4 signaling is essential for proper cardiovascular development, and may mediate bi-directional communication between arteries and veins. Our current studies include a further analysis of ephrinB2-EphB4 function in angiogenesis, using cell type-specific gene targeting; and experiments to understand the developmental origins of vessel identity. We are also exploring the existence and nature of reciprocal interactions between the developing nervous system and circulatory system.
A new initiative in the lab has begun to move from the area of nervous system development to adult neural function. We are interested in developing and applying novel molecular biological tools to map and manipulate the neural circuits involved in innate behaviors. Our initial studies have focused on innate fear as a behavioral system. We are developing novel behavioral paradigms to study defensive responses to unconditioned unimodal sensory stimuli, and are using immediate early genes to map the brain regions that are active in these paradigms. Efforts to identify genes expressed in these regions, both constitutively and in an activity-dependent manner, are also underway, in parallel with the development of new methods to trace axonal connections and, in collaboration with the Lester laboratory, to reversibly silence neuronal activity. Together these tools should permit the mapping and functional manipulation of the neural circuits underlying various forms of fear.
In parallel with these studies in mice, we have initiated conceptually similar experiments in the fruitfly, Drosophila melanogaster. Our goal is to identify simple and robust innate behaviors, and then perform unbiased “anatomical” and genetic screens to map the neuronal circuits and identify the genes that control these behaviors. This dual approach will provide an opportunity to integrate molecular genetic and circuit-level approaches to understanding how genes influence behavior. The “anatomical” screen exploits the availability of “enhancer trap” lines in which the yeast transactivator protein GAL4 is expressed in specific subsets of neurons, and a conditional (temperature-sensitive) neuronal silencer gene that prevents synaptic transmission. Currently we have developed assays for an innate avoidance response triggered by a conspecific putative alarm pheromone (fly “fear”), as well as for arousal intensity and hedonic valence, two important axes underlying emotional states in humans.
