Azad Bonni

Department of Pathology
Harvard Medical School
New Research Building, 8th Floor
77 Ave. Louis Pasteur
Boston, MA 02115
Tel: (617) 432-4104
Fax: (617) 432-4101
Email: azad_bonni@hms.harvard.edu
Web Page: The Bonni Lab Page
3 postdoctoral fellows, 5 graduate students

Our research is focused on identifying the key mechanisms that govern neuronal connectivity in the brain. We are also interested in determining how these fundamental mechanisms are deregulated in brain diseases. Axonal and dendritic morphogenesis culminating in synapse formation as well as neuronal death represent critical developmental events that control the assembly of neural circuits in the mammalian brain. To elucidate the molecular basis of these fundamental developmental events, we are employing a combination of molecular and cell biological, biochemical, and genetic approaches in the rodent cerebellar cortex.

We have uncovered a pivotal function for the ubiquitin ligase, Cdh1-anaphase promoting complex (Cdh1-APC), in the control of axon growth and patterning. We have also identified that the transcriptional regulators SnoN and Id2 as critical substrates of neuronal Cdh1-APC in the regulation of axonal morphogenesis. In other studies, we have found that sumoylation of the transcription factor MEF2 drives postsynaptic dendritic differentiation. Our findings highlight the importance of nuclear ubiquitylation and sumoylation pathways in the cell-intrinsic control of neuronal connectivity.

In addition to axonal and dendritic morphogenesis and synapse development, neuronal death ensures the proper wiring of the brain during normal development. The focus of our research in this area is to identify neural-specific mechanisms of cell death. As part of this effort, we have identified a function for the mitotic kinase Cdk1 in apoptosis of postmitotic neurons and a mechanism by which the mitochondrial cell death machinery is activated specifically in neural cells. We have also identified a link between the MST family of kinases and the transcription factor FOXO3 that promotes cell death in neurons.

As the molecular underpinnings of brain development are unraveled, the more opportunities we will have to gain novel insights in the pathogenesis of brain diseases. As part of this approach, we are carrying out studies of brain tumors based on our understanding of mechanisms regulating cell differentiation in the developing brain.

References:

• Konishi Y, Stegmüller J, Matsuda T, Bonni S, Bonni A. Cdh1-APC controls axonal growth and patterning in the mammalian brain. Science 2004, 303:1026-30.
• Stegmüller J, Konishi Y, Huynh MA, Yuan Z, DiBacco S, Bonni A. Cell-intrinsic regulation of axonal morphogenesis by the Cdh1-APC target SnoN. Neuron 2006, 50: 389-400.
• Shalizi A*, Gaudillière B*, Yuan Z, Shirogane T, Stegmüller J, Ge Q, Tan Y, Schulman B, Harper JW, Bonni A. (*equal contribution). A calcium-regulated MEF2 sumoylation switch controls postsynaptic dendritic differentiation. Science 2006, 311:1012-1017.
• Lehtinen M*, Yuan Z*, Boag P, Yang Y, Villen J, Becker E, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A. (*equal contribution). A conserved MST-FOXO signaling pathway mediates oxidative stress responses and extends lifespan. Cell 2006, 125: 987-1001.