Biomedical subjects

Colleen M Witt

Publications and source records attributed to Colleen M Witt.

6 recordsLinked to original sources

PubMed2005

Tracking thymocyte migration in situ.

The dynamic process of thymocyte migration can now be visualized in real-time and in the context of the native thymic environment. With improved computational resources, key information can be extracted from real-time imaging data and the migratory behaviors of developing thymocytes can be quantitated. The extraction and exploitation of three dimensional data through time is providing new insight into the nature and regulation of intrathymic migration. In this review we discuss this interdisciplinary approach and the promise it holds for the study of thymocyte migration in situ.

Animals↗

PubMed2005

Directed migration of positively selected thymocytes visualized in real time.

Development of many vertebrate tissues involves long-range cell migrations. In most cases, these migrations have been inferred from analysis of single time points and the migration process has not been directly observed and quantitated in real time. In the mammalian adult thymus, immature CD4+ CD8+ double-positive (DP) thymocytes are found in the outer cortex, whereas after T cell antigen receptor (TCR) repertoire selection, CD4+ CD8- and CD4- CD8+ single-positive (SP) thymocytes are found in the central medulla. Here we have used two-photon laser-scanning microscopy and quantitative analysis of four-dimensional cell migration data to investigate the movement of thymocytes through the cortex in real time within intact thymic lobes. We show that prior to positive selection, cortical thymocytes exhibit random walk migration. In contrast, positive selection is correlated with the appearance of a thymocyte population displaying rapid, directed migration toward the medulla. These studies provide our first glimpse into the dynamics of developmentally programmed, long-range cell migration in the mammalian thymus.

Animals↗

PubMed2005

Thymopoiesis in 4 dimensions.

Developing T cells undergo long-range migrations in the thymus that are tightly linked to their developmental program. In this review, we discuss the anatomical positioning of developing T cells in the thymus, review what we know about how cells move in the thymus, and point out unresolved questions. We also discuss new imaging technologies and interdisciplinary approaches and discuss how the promise they offer to addressing these questions.

Animals↗

PubMed2004

The ins and outs of CCR7 in the thymus.

Although it is widely supposed that chemokines play a role in the thymus, most existing evidence is circumstantial. In this issue, two groups provide direct evidence that the chemokine receptor CCR7 is required for normal thymocyte migration (Ueno, T., F. Saito, D. Gray, S. Kuse, K. Hieshima, H. Nakano, T. Kakiuchi, M. Lipp, R. Boyd, and Y. Takahama. 2004. J. Exp. Med. 200:493-505; Misslitz, A., O. Pabst, G. Hintzen, L. Ohl, E. Kremmer, H. T. Petrie, and R. Forster. 2004. J. Exp. Med. 200:481-491). The two papers focus on distinct and opposite migration events, an early outward migration and a later inward migration. Together these papers provide a fascinating picture of the complex role of CCR7 in orchestrating thymocyte migration.

Cell Movement↗

PubMed2003

Notch2 haploinsufficiency results in diminished B1 B cells and a severe reduction in marginal zone B cells.

Recent studies have implicated a role for Notch in the generation of marginal zone (MZ) B cells. To further investigate the role of Notch in the B cell lineage, we have analyzed the effects of reduced Notch2 signaling in mice expressing one functional allele of Notch2 (Notch2(+/-)). Notch2(+/-) mice have reduced B1 B cells of the peritoneal cavity and show a severe reduction in MZ B cells of the spleen. The reduction in MZ B cells was not due to the disruption of splenic architecture, disregulated terminal differentiation, nor to increased apoptosis within the MZ B cell compartment. Rather, our data suggest that Notch2 haploinsufficiency leads to impaired development of MZ B cells, possibly by impacting the formation of immediate MZ B precursors. These results provide evidence that Notch2 plays a determining role in the development and/or the maintenance of B1 B and MZ B cells.

Alleles↗

PubMed2003

Activated Notch2 potentiates CD8 lineage maturation and promotes the selective development of B1 B cells.

Although studies have shown that the Notch2 family member is critical for embryonic development, little is known concerning its role in hematopoiesis. In this study, we show that the effects of an activated form of Notch2 (N2IC) on the T-cell lineage are dosage related. High-level expression of N2IC results in the development of T-cell leukemias. In contrast, lower-level expression of N2IC does not lead to transformation but skews thymocyte development to the CD8 lineage. Underlying this skew is a dramatic enhancement in positive selection and CD8SP maturation. N2IC permits early B-cell development but blocks the maturation of conventional B2 cells at the pre-B stage, which is the limit of endogenous Notch2 protein expression in developing B cells. Most strikingly, while B2 B cell development is blocked at the pre-B-cell stage, N2IC promotes the selective development of LPS-responsive B1 B cells. This study implicates a role for Notch2 in the maturation of the CD8 lineage and suggests a novel function for Notch2 in the development of the B1 B-cell subset.

Animals↗