Massachusetts General Hospital

Anne C. Hart, PhD
Associate Professor of Pathology
Harvard Medical School

Associate Geneticist
Center for Cancer Research

Research Summary

The Hart laboratory uses C. elegans as a model system to answer questions in two broad areas:

• The role of the Notch pathway in aging, behavior and development
• 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 recently identified a new family of conserved, soluble Notch ligands that regulate behavior, cell fate specification, and lifespan. In the adult nervous system, these soluble ligands act upon Notch receptors to modulate behavior in response to changes in the environment. Using a wide variety of techniques, we are examining the direct targets of Notch signaling in mature neurons which we expect are critical for neuronal function in all nervous systems. The soluble Notch ligands also act in developmental cell fate decisions. Using genetic, molecular and biochemical analysis, we are examining how the new soluble ligands regulate Notch receptor activation during vulval development. We are also addressing how these new Notch ligands coordinately regulate 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: Huntingtons 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.

Anne C. Hart, PhD
Principal InvestigatorGroup Members

• Amy Walker, PhD
• Maria Dimitriadi, PhD
• Geetika Kalloo
• Garard Somers
• Ed Anderson
• Mark Corkins
• Juan Carmona, BS
• Rhonda Hyde, BS

Publications

View a list of publications by researchers at the Hart Laboratory

Hart Laboratory

Phone: 617-726-5618
Email: hart@helix.mgh.harvard.edu