Journal Club: Developmental Biology, Stem Cell Biology, Cancer Biology, and Biophysics

Graduate Division

DEVELOPMENTAL BIOLOGY: Emergence of hematopoietic stem and progenitor cells involves a Chd1-dependent increase in total nascent transcription. Koh, F.M., et al. (Ramalho-Santos, M.). PNAS. 2015. Epub ahead of print.

The long-lasting hematopoietic stem cells that occupy the bone marrow and proliferate and differentiate into new blood cells throughout life arise from endothelium in the embryo. Much is unknown about how this endothelial-to-hematopoietic transition is controlled.

Here the Ramalho-Santos lab reports that the chromatin-remodeling protein Chd1 is essential for this process. Deletion of the Chd1 gene in endothelium leads to anemia and death of the mouse embryo fifteen days after conception. Interestingly, when the gene is deleted hematopoietic cells, the mice survive.

The researchers found that as the endothelial cells transition to being hematopoietic, there is an overall increase in transcription. It is this increase that requires Chd1. Once the transition is complete, Chd1 is no longer essential.

STEM CELL BIOLOGY: Opposing activities of Notch and Wnt signaling regulate intestinal stem cells and gut homeostasis. Tian, H., et al. (Klein, O.D.). Cell Rep. 2015. Epub ahead of print.

The interior surface of the small intestine is covered with numerous projections called villi, covered with a single layer of epithelial cells. These cells differentiate from stem cells located at the base of the villi and make their way up the villi before being shed.

Previous research has shown that one of these stem cells can differentiate into both absorptive cells and secretory cells, but what controls the balance between these two fates has been unclear. In this paper, the authors show that a balancing act between two signaling pathways is crucial.

Blocking Notch receptors leads to excessive production of secretory cells due to increased Wnt pathway activity. They show that if the Wnt pathway is also dampened, balance is restored. The authors suggest this Notch-Wnt interaction may be important in other types of stem cells.

CANCER BIOLOGY: Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia. Chen, Z., et al. (Müschen, M.). Nature. 2015. Epub ahead of print.

Acute lymphoblastic leukemia (ALL) predominantly occurs in children, in which case there is a greater than 80 percent chance of a cure. For adults who develop ALL, however, survival rates are considerably worse.

Targeted therapy of one major type of ALL has focused on dampening the BCR signaling pathway in order to cause cell death. In this paper, Chen and colleagues investigated the effect of heightening this signaling, which was already known to lead to cell death in normal B cells.

They found that using an inhibitor of SHIP1 on ALL cells led to increased activity of the Syk tyrosine kinase and that this was necessary and sufficient for cell death. They propose this as a new strategy for targeted therapy of ALL.

BIOPHYSICS: A systematic comparison of mathematical models for inherent measurement of ciliary length: how a cell can measure length and volume. Ludington, W.B., et al. (Marshall, W.F.). Biophys J. 2015. 108(6):1361-1379.

Different cells show great variability in size and shape. How does a cell know what size it is? How does it make sure its different parts are the correct size?

The Marshall group focused on one aspect of this question in this paper, investigating how cells regulate the size of cilia and flagella. Previous work showed that an active transport process is important in regulating flagella size, but not how it does so. They generated and tested various mathetmatical models based on different conceptual models. Each model predicted how length and intraflagellar transport would be related.

Examining available experimental data, they found three models that made good predictions. Upon generating additional data using photobleaching experiments, they narrowed this down to two: an ion current model and a diffusion-based model.