Azad Bonni, Ph.D., M.D.

Associate Professor of Pathology

Harvard Medical School
Armenise Building
200 Longwood Avenue
Boston, MA 02115
Tel: (617) 432-4104
Fax: (617) 432-4101
Email: azad_bonni@hms.harvard.edu
Website: The Bonni Lab Page
7 Predocs 3 Postdocs 5 completed Ph.D.s

We are interested in the signaling and transcriptional mechanisms that regulate cell survival and differentiation in the mammalian brain and how abnormalities of these pathways contribute to neurologic disorders. We have begun to elucidate the intracellular mechanisms that specifically regulate the development of axons and dendrites in granule neurons of the developing mammalian cerebellum. We have identified a novel function for the transcription factor NeuroD in the specification of dendrites. We have also defined a CaMKII-NeuroD signaling pathway that mediates neuronal activity-dependent dendritic growth. It will be important to determine how the CaMKII-induced phosphorylation of NeuroD at key sites including Serine 336 regulates NeuroD function, to identify targets of NeuroD that specifically promote dendritic growth, and to determine if NeuroD is the target of other extrinsic signals that regulate dendritic growth.

We have also uncovered a novel role for the ubiquitin ligase, Cdh1-anaphase promoting complex (Cdh1-APC), in the control of axon growth and patterning. Cdh1 knockdown by RNAi specifically promotes the growth of axons. In cerebellar slice overlay assays and in vivo RNAi experiments in the postnatal cerebellum, Cdh1 was found to cell-autonomously control the layer-specific growth of granule neuron axons and parallel fiber patterning. These findings have raised several key questions. What is the mechanism by which Cdh1-APC controls axonal growth? How is Cdh1-APC regulated in neurons? What is the role of Cdh1-APC in neurons upon exposure to extrinsic signals that regulate axonal growth? Addressing these questions will significantly enhance our understanding of axonal morphogenesis in the developing brain. In addition, our research should also provide the foundation for the development of drugs that might ultimately be used to stimulate axonal regeneration following injury and disease.

Other projects in the laboratory are aimed at characterizing the mechanisms by which pro-apoptotic kinases trigger neuronal cell death. In addition, we are interested in the mechanisms that underlie neural stem cell differentiation and how abnormalities of these mechanisms might contribute to the pathogenesis of brain tumors.

Selected References:

• Gaudillière B, Konishi Y, de la Iglesia N, Yao G, Bonni A (2004) A CaMKII-NeuroD signaling pathway specifies dendritic morphogenesis,Neuron 41(2):229-41.
• Konishi Y, Stegmüller J, Matsuda T, Bonni S, Bonni A (2004) Cdh1-APC controls axonal growth and patterning in the mammalian brain,Science, 303:1026-30.
• Stegmüller J, Bonni A (2005) Moving past proliferation: new roles for Cdh1-APC in postmitotic neurons. Trends Neurosci. 28:596-601.
• Shalizi A, Gaudillière B, Yuan Z, Shirogane T, Stegmüller J, Ge Q, Tan Y, Schulman B, Harper JW, Boni A (2006) A calcium-regulated MEF2 sumoylation switch controls postsynaptic dendritic differentiation, Science 311(5763):1012-7.
• Lehtinen M, Yuan Z, Boag P, Yang Y, Villen J, Becker E, DiBacco S, de la Iglesia N, Gygi S, Blackwell TK, Bonni A (2006) A conserved MST-FOXO signaling pathway mediates osidative stress responses and extends lifespan, Cell 125(5):987-1001.
• Lasorella A, Stegmüller J, Guardavaccaro D, Liu G, Rothschild G, de la Torre-Ubieta L, Pgano M, Bonni A, Ivarone A (2006) Degradation of Id2 by the anaphase promoting complex couples control of cell cycle and axonal growth, Nature 442(7101):471-4.
• Iwase S, Lan F, Bayliss P, de la Torre-Ubieta L, Huarte M, Qi H, Whetstine J, Bonni A, Roberts TM, Shi Y (2007) The X-linked mental retardation gene SMXC/JARID1C defines a family of histone H3 lysine 4 demethylases, Cell 128:1077-1088.