Anne C. Hart

Department of Pathology
Massachusetts General Hospital
Bldg. 149, Room 7212
13th Street
Charlestown, MA 02129
Tel: (617) 726-5618
Fax: (617) 724-6919
Email: hart@helix.mgh.harvard.edu
Website: The Hart Lab Page
Website 2:The Hart Lab Page 2

The Hart laboratory uses C. elegans as a model system to answer questions in two broad areas: 1) the role of the Notch pathway in aging, behavior and development and 2) the molecular mechanisms underlying neurodegenerative diseases.

One focus of the lab is the Notch pathway. The role of the Notch signaling in cell fate specification has been clearly established and Notch receptors are conserved across species. We have a new family of conserved, soluble Notch co-ligands that regulate behavior and cell fate specification. In the adult nervous system, these co-ligands act upon neuronal Notch receptors to modulate behavior in response to changes in the environment. Using a wide variety of techniques, we are identifying and characterizing examining the direct targets of Notch signaling in mature neurons that we expect are critical for neuronal function in all nervous systems. The newly identified Notch co-ligands also act in developmental cell fate decisions. Using genetic, molecular and biochemical analysis, we are examining how these proteins regulate Notch receptor activation during vulval development.  We are also addressing how these Notch co-ligands regulate stress response, C. elegans lifespan and germ cell proliferation.

The other focus of the laboratory is modeling human neurodegenerative diseases in C. elegans. Two diseases are currently under analysis: Huntington’s disease and spinal muscular atrophy. Given the strong homology between humans and invertebrates, we hope to understand the pathological mechanisms underlying these diseases using genetic techniques available in C. elegans. In humans, expansion of a polyglutamine domain in the Huntington's gene causes neurodegeneration, dementia and chorea.  We have developed a C. elegans model for Huntington's and other polyglutamine diseases by expression of an N-terminal fragment of human huntingtin containing an expanded polyglutamine domain in C. elegans neurons.  Using the genetic and molecular tools available in C. elegans, we are elucidating the cellular and molecular basis of cell death and degeneration in this system. Spinal muscular atrophy (SMA) results in loss of anterior spinal cord motor neurons with consequent muscular atrophy. It is unclear why specific motorneurons are affected in SMA. Loss of the C. elegans homolog, SMN-1, results in developmental delays and lethality. Genome-wide RNAi screens in C. elegans have revealed conserved genes that are critical for SMN pathology and polyglutamine toxicity. These conserved pathways will be validated in other vertebrate and invertebrate models to confirm their role in neurodegenerative disease.

References:

• Komatsu H, Chao MC, Larkins-Ford J, Corkins ME, Somers GA, Tucey T, Dionne HM, White JQ, Wani K, Boxem M, Hart AC OSM-11 facilitates LIN-12 Notch signaling during C. elegans vulval development 2008 PLoS Biology In press.
• Ferkey D, Hyde R, Haspel G, Dionne HM, Hess HA, Suzuki H, Schafer WR, Koelle MR, Hart AC C. elegans G Protein Regulator RGS-3 Controls Sensitivity to Sensory Stimuli 2007 Neuron 53(1):39-5.
• E.A. Bates, M. Victor, M.J. Alkema, A.K. Jones, Y. Shi, H.R. Horvitz, and A.C. Hart. 2006. Differential contributions of Caenorhabditis elegans histone deacetylases to huntingtin polyglutamine toxicity. Journal of Neuroscience 26: 2830-2838.
• M.Y. Chao, J. Larkins-Ford, T.M. Tucey, and A.C. Hart 2005. lin-12 Notch functions in the adult nervous system. BMC Neuroscience 6:45.