HSCI Science Update: May-June 2010

June 30, 2010

WT1 Targets Provide Insights Into Kidney Development

The Wilms' tumor suppressor 1 gene (WT1) is an important factor in development of the progenitors of the nephron, the basic structural and functional unit of the kidney, during kidney development. In order to identify the factors that the WT1 gene targets and in turn gain a better understanding of nephron progenitor differentiation, HSCI Principal Faculty member Jordan Kreidberg, MD, and fellow researchers used methods to identify over 1500 genes bound by WT1. Functional assays on the identified target genes revealed signaling pathways involved in directing nephron progenitor fate during kidney development. This increased understanding of the process of kidney formation will help provide insights into treating kidney disease and injury.

Hartwig, S., Ho, J., Pandey, P., Macisaac, K., Taglienti, M., Xiang, M., Alterovitz, G., Ramoni, M., Fraenkel, E., Kreidberg, J.A. (2010) Genomic characterization of Wilms' tumor suppressor 1 targets in nephron progenitor cells during kidney development. Development 137, 1189-203.

JAK Be Nimble; Researchers Elaborate Role of JAK2 in Blood Diseases

Myeloproliferative diseases are a group of bone marrow diseases characterized by excess production of cells. One of the diseases in this group, human polycythemia vera (PV), is associated in a majority of cases with mutations in the JAK2 signaling protein. In order to better understand the effects of these mutations on hematopoietic stem and progenitor cells in myeloproliferative disease, HSCI Principal Faculty member Benjamin Ebert, MD, and colleagues have described a mouse model with a JAK2 mutation that resembles PV. They find that the mutation in these mice has distinctly different effects on the hematopoietic stem cell compartment and the myeloid progenitor populations. Further, the researchers found that treating mice with an inhibitor of the mutant kinase removed the disease phenotype but did not remove the disease initiating cells. These results suggest that the disease cells may not be targeted by the kinase inhibitor and normal and mutant stem cells may have different molecular networks, with the JAK2 mutation not necessarily being the disease-initiating mutation. These findings have exciting implications for therapeutic approaches toward these types of bone marrow diseases and shed light on the role of JAK2 in HSC differentiation and function.

Mullally, A., Lane, S.W., Ball, B., Megerdichian, C., Okabe, R., Al-Shahrour, F., Paktinat, M., Haydu, J.E., Housman, E., Lord, A.M., Wernig, G., Kharas, M.G., Mercher, T., Kutok, J.L., Gilliland, D.G., Ebert, B.L. (2010). Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 17, 584-96.

Cellular Windows for Reprogramming by Nuclear Transfer Wide and Multitudinous

Reprogramming by nuclear transfer is a means by which to reprogram somatic cells to totipotency. In order to gain a better understanding of the reprogramming process and the associated cellular requirements, HSCI Principal Faculty member Kevin Eggan, PhD, and fellow researcher Dieter Egli, PhD, investigated nucleus donor and recipient cells at different cell cycle and developmental stages. They learned that the reprogramming process may be more flexible than we thought as many cell cycle stages are permissive for reprogramming provided the necessary nuclear factors are available. Such elaboration of the process of nuclear transfer not only informs our basic understanding of reprogramming biology but also provides researchers with more information with which to optimize nuclear transfer for potential applications such as creating patient-specific cell lines.

Egli D, Eggan K. (2010). Recipient cell nuclear factors are required for reprogramming by nuclear transfer. Development 37, 1953-63. Epub 2010 May 12.