Description of Research Expertise

Research Interests
- Stem Cell Function
- Developmental Patterning

Key words: Stem Cells, Wnt, Hedgehog, Notch, Development, Cell Signaling, embryo.

Description of Research

Stem Cell Function



1. Stem Cell Function http://www.med.upenn.edu/sdinardo/Stem%20Cells.html
Stem cells hold the key to the continual renewal of many tissues in our bodies. In addition, the in vitro manipulation of stem cells holds much promise in regenerative medicine. Unfortunately, there are severe limitations in our knowledge of the regulation of stem cells. These limitations compromise both our understanding of normal tissue renewal, as well as the facility with which stem cell populations can be grown and manipulated in vitro. We are trying to remove such limitations by studying stem cells within their natural environment, the niche by using Drosophila spermatogenesis as a model stem cell system. This allows us to bring to bear modern approaches to uncover new regulatory factors that govern stem cell behavior.

Through genomic-scale analyses, we have identified several genes whose expression is enriched in stem cells or their niche cells, and are studying their function. These include a transcriptional repressor, zfh1, that we find maintains somatic stem cell fate, a pioneer protein, lines, that we find keeps stem cells from differentiating into niche cells, and a novel secreted factor necessary for continued survival of germline stem cells. But our contributions extend beyond the simple identification of new regulator factors. They have also revealed conceptually new facets of control over stem cell lineages. For example, we know now that two different types of stem cells communicate in a common niche; we know that as a stem cell pool is initially established in a tissue, a regulatory pathway parses some cells as stem cells and others as niche cells. In these, and similar other examples, we can now attack how these conceptually interesting facets of stem cell biology are controlled.
Given the deep conservation of developmental mechanisms across species, we are confidant that concepts revealed by our studies in the fruitfly will apply to some mammalian stem cell lineages.


Cell Biology of Developmental Patterning



2. The Cell Biology of Developmental Patterning http://www.med.upenn.edu/sdinardo/Patterning.html
While Developmental Biology has had much success in uncovering the regulatory hierarchies that govern pattern, there has been less success in figuring out how sheets of cells respond to organizing signals and actually make that pattern. Thus, how do signaling pathways, such as Notch, EGF-receptor, Wnt and Hedgehog, cause changes in the cytoskeletal biology of responding cells?

We study three cell biological outputs of developmental signals. The first involves the dynamic remodeling of cell-cell interfaces in order to align cells within an epithelium. Such “morphogenesis” is a fundamental feature of constructing all tissues, yet it is little understood. The second involves another process fundamental to all epithelial cells: the shaping of actin-based apical protrusions. Such protrusions underlie brush border microvilli, sensory bristles or stereocilia, and constructing these protrusions properly and organizing their pattern across an epithelium is directly responsible for tissue function. Finally, the third area address how epithelial cells become polarized within the plane of the tissue. This is a fundamental problem affecting all epithelia. The genes involved are conserved, yet the mechanism remains unclear just how specific regions within a cell are singled out, and how this information is choreographed across a field of cells.


Rotation Projects for 2009-2010
Stem Cell Biology Projects:
Students will participate in the genetic and genomic identification of factors that govern the balance between self-renewal and differentiation. With the completion of the Drosophila genome sequence, we have used microarray and a GFP protein “exon trapping” technology to derive a list of genes enriched in stem cells and the stem cell niche. Students can participate in functional studies of any of several novel genes that each effect the behavior of stem cells. Collaborative opportunities also exist for translational work, where students can explore whether our discoveries in Drosophila apply to mammalian spermatogenesis as well as other stem cell systems investigated here at Penn.

Developmental Patterning Projects:
Students will participate in the investigation of how organizer signaling pathways control the cell biological responses of their target cells. This involves examining the cytoskeletal changes that occur during cell differentiation in real-time, using live embryo imaging, as well as by other high resolution imaging and microscopy techniques. These approaches are complemented by molecular manipulation of target proteins of these signaling pathways, such as small GTPases, polarity and adhesion proteins and cytoskeletal components.

Lab personnel:
Graduate Students - Stacie Dilks, Bob Simone, Tishina Okegbe
Postdoctoral Fellow – Judith Leatherman
Research Assistant – Seth Donoughe
Undergraduate Assistants - Steven Chen, John Kouch, Benita Chumo