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Guidos Lab
Guidos Lab

Lymphocyte Development

Functions of Notch-Fringe Interactions in Lymphocyte Development and Homeostasis

Signaling through the Notch-1 receptor is required to induce T lineage specification and also to suppress B cell development in the thymus. Subsequently, Notch-1 activation regulates survival and maturation of early T cell progenitors as they migrate through the thymic cortex. Members of two structurally distinct families of Notch ligands, Delta-like and Jagged, are widely expressed in lymphoid tissues. We have shown that Lunatic Fringe critically regulates Notch-1 activation during multiple early stages of intrathymic T cell development (Immunity, 2001; Nature Immunology, 2005).

Our genetic approaches have revealed that Lunatic Fringe endows T cell progenitors with the ability to compete for functionally limiting Delta-like Notch ligands in specific micro-environmental niches. Our current goals are to: 1) identify the genetic targets of Notch-1 signaling in early T cell progenitors, 2) identify the micro-environmental niches where intrathymic Notch-1 activation takes place, and 3) determine how dysregulation of Notch-1 signaling causes T cell leukemia.

In contrast to T cell development, B cell development in the bone marrow does not require Notch activation. Newly formed B cells migrate from the bone marrow to the spleen, where most develop into follicular (Fo) B cells, the major recirculating T-dependent B cell subset. However, a small subset develops into marginal zone (MZ) B cells in response to Notch-2 activation by Delta-like1. Unlike Fo B cells, MZ B cells are sessile cells that reside near the marginal sinus in the red pulp of the spleen where they can be activated by bacterial cell wall polysaccharides in a T cell-independent fashion, thus providing crucial protection against bacterial sepsis.

Our current goals are to: 1) determine which cells in the spleen present Dll-1 to induce MZ B cell development, 2) determine how Fringe proteins regulate Notch-2-Dll-1 interactions during MZ B cell development, 3) investigate molecular mechanisms by which Notch-2 regulates MZ B cell development, and 4) determine how Fringe proteins regulate Notch-Dll-1 interactions to control T cell activation and homoestasis in peripheral lymphoid tissues.

Experimental Approaches:

We use a combination of genetic approaches (transgenic mice and retroviral/lenti-viral gene transfer; constitutive and conditional knock-out mice) and biochemical approaches to define the functions of particular genes and proteins in lymphocyte development and homeostasis. To study developmental potential and cell lineage commitment, we use adoptive transfer systems (bone marrow chimeras, intrathymic and intrafemoral injections) as well as in vitro cell culture systems. We also utilize lacZ and GFP reporter mouse strains to visualize cells expressing particular Notch receptors and ligands as they develop and interact in vivo.

Positions available: Positions are available for graduate students, and post-doctoral fellows with appropriate background and expertise.

Funding Support:
Canadian Institutes of Health Research