The major interests of our lab are to understand the molecular control of neuronal shape and neural circuit development.

Neurons show an incredible diversity of morphologies, yet for individual types of cells morphology is usually very characteristic. How is this diversity (and stereotypy) achieved? We use molecular and genetic approaches to examine how different neurons, such as those shown above, acquire their different branching patterns during development. Previous work has implicated transcriptional regulation in the control of morphological diversity of these cells. In particular, we showed that different morphological classes of dendritic arborization (da) neurons express different levels of the homeodomain transcription factor Cut. The finding that loss of function and gain of function manipulations altered dendrite morphology in characteristic ways indicates that these levels are important for the generation of diverse morphological patterns.

Dendritic arbors fill characteristic territories, and these territories determine where and how they receive sensory or synaptic input. One means by which neurons establish their territories is through dendrite-dendrite repulsion. We are interested in the cellular and molecular mechanisms of tiling (dendritic repulsion between cells of the same type) and self-avoidance (repulsion betwen sister branches from the same neuron). In collaboration with Larry Zipursky's lab at UCLA we have recently shown that Dscam (for Down syndrome cell adhesion molecule) is a key regulator of dendrite self-avoidance. By alternative splicing Dscam generates over 38,000 distinct isoforms and each appears capable of homophilic binding. Normally sister dendrites do not cross each other. However, when individual neurons are made mutant for Dscam, their arbors cross extensively. Dscam isoform diversity appears dispensible for self-avoidance, as individual isoforms can rescue this mutant phenotype. What is the role of Dscam diversity in these dendrites? It seems likely based on studies of other neuronal types, that individual neurons will express many different Dscam isoforms in a stochastic fashion. It might be that the only time that two dendrites would express the same exact isoforms is if they originated from the same cell. If this is the case, we reasoned that forcing two different cells to express the same predominant isoform might cause their arbors to behave as though they were "self" and avoid crossing each other. Indeed, we found that overexpression of individual Dscam isoforms in dendrites that normally overlap leads to segregation of their territories. Thus, Dscam diversity ensures that dendrites of different cells don't engage in repulsive behavior with each other, and thus that they can share their territories. This self vs. non-self recognition system is likely important widely in the developing nervous system, where arbors of many cells intermingle with one another.








Forward genetic approaches at single neuron resolution provide a powerful means by which to identify new genes involved in the development of dendrites and axons. The recent completion of such a screen will allow exploration of the molecular mechanisms of dendritic branching, tiling, and territory formation. We have also generated an anatomical map of somatosensory axon projections within the CNS, and identified several loci that seem to be important for generating this axon pattern. This work will serve as a foundation for studies of the assembly and function of somatosensory circuits.








Our research is made possible by funding from:

Esther A. and Joseph Klingenstein Fund

Gatsby Initiative in Brain Circuitry

Irma T. Hirschl/Monique Weill-Caulier Trust

NIH/NINDS

Searle Scholars Program