During development, cells differentiate into well-defined patterns through an orchestrated program in space and time. This requires a combination of intercellular signaling, enabling cells to coordinate their differentiation, and intracellular genetic circuits, allowing the cells to process external signals. While much is known about the components involved in developmental patterning (signaling molecules, genes, and proteins), it remains unclear how these components combine as genetic circuits to generate patterns. My long term research goal is to understand how developmental programs are encoded and executed by the underlying genetic circuit within each cell. This goal will be pursued by specifically addressing the following questions: What is the relationship between circuit architecture and the developmental patterns formed? How do the properties of the signaling system (and other components) affect the patterning processes? How is cell morphology controlled or affected by the developmental processes?

Elucidation of Notch-dependent developmental patterns

We address these questions in the context of fine grained developmental patterns in which neighboring cells adopt different fates (such as differentiation of neural precursors into neurons and glia). In metazoans, the canonical signaling pathway that enables coordination between neighboring cells is the Notch signaling pathway. Signaling between neighboring cells is mediated by the interaction between Notch receptors in one cell and membrane-tethered Delta ligands in its neighbor. Using a reconstitution of the Notch signaling pathway in cell culture combined with quantitative time lapse microscopy and mathematical modeling, we have recently shown (Sprinzak et al, Nature 2010) that interactions between Notch and Delta in the same cell (cis-interaction) also play an important role in the generation of fine grained developmental patterns such as sharp boundary formation and lateral inhibition patterning (checkerboard like).

Some of our research directions include:

1. Determine the requirements and constraints in the formation of Notch mediated fine grained patterns such as lateral inhibition patterns and sharp boundaries.

2. Measure Notch signaling dynamics at the single cell and subcellular levels.

3. Examine the role of cell/tissue morphology and cell proliferation in Notch-dependent pattern formation.

We use advanced quantitative time lapse microscopy, micropatterning techniques, and mathematical modeling to measure and analyze quantitative properties of the Notch signaling pathway and Notch dependent patterning processes. We also use synthetic biology to recreate genetic circuits in mammalian cells and study their dynamics.

• Cis interactions between Notch and Delta generate mutually exclusive signaling states, D. Sprinzak, A. Lakhanpal, L. LeBon, L. A. Santat, M. E. Fontes, G. A. Anderson, J. Garcia-Ojalvo, M. B. Elowitz, Nature. 2010 May 6;465(729)
  
• Reconstruction of genetic circuits, D. Sprinzak and M. Elowitz, Nature 438(7067), 443-8 (2005) Review.