Azad Bonni Research Abstract

The major goal of research in the Bonni laboratory is to identify key mechanisms and principles that govern the establishment of neuronal connectivity in the brain. We are also interested in how deregulation of these mechanisms contributes to the pathogenesis of neurological and psychiatric diseases. The morphogenesis and differentiation of axons, dendrites, and synapses represent critical events that orchestrate neuronal connectivity in the brain. To elucidate the molecular basis of these fundamental developmental events in neurons, we are employing a combination of biochemical, molecular and cell biological, imaging, and genetic approaches in the rodent brain.

During the past few years, we have discovered some of the first key cell-intrinsic transcriptional and ubiquitin pathways that regulate neuronal morphogenesis and synaptic connectivity in the mammalian brain. Our studies on the role of transcriptional mechanisms support the concept that different transcription factors are dedicated to distinct aspects of neuronal development, from axon specification and neuronal positioning to axon and dendrite growth and pruning to synapse differentiation. In early studies on the role ubiquitin signaling in neuronal development, we identified a key role for the ubiquitin ligase Cdh1-anaphase promoting complex (Cdh1-APC) in the control of axon growth and patterning (Konishi et al. Science 2004). Cdh1-APC operates in the nucleus of differentiating neurons to regulate transcriptional regulators and consequent programs of gene expression dedicated to axon morphogenesis. In more recent studies, we have identified novel functions for the related ubiquitin ligase Cdc20-APC in neuronal morphogenesis and connectivity. Remarkably, Cdc20-APC acts at the centrosome to promote the elaboration of dendrite arbors. We have also recently uncovered a specific role for the protein kinase CaMKII in the phosphorylation and consequent inhibition of Cdc20-APC at the centrosome, thereby triggering a switch from dendrite growth and elaboration to dendrite retraction and pruning in the brain. In other studies, we have discovered that Cdc20-APC drives the differentiation of presynaptic sites.

We are currently building on our discoveries to provide novel insights into the molecular underpinnings of brain development. In addition, we have a launched a new area of research in the laboratory at the interface of neurobiology with neurology and psychiatry, in which we aim to identify the molecular pathogenic mechanisms underlying autism spectrum disorders and mental retardation.