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In brief: March 2002

Signal Transduction

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An allelic series at the PDGR locus indicates unequal contributions of distinct signaling pathways during development.
Klinghoffer, R. A. et al. Dev. Cell 2, 103–113 (2002) [PubMed]

It is an aim of the signal-transduction field to determine which signalling proteins enable receptor tyrosine kinases (RTKs) to stimulate specific signalling pathways during development. To investigate this, Klinghoffer et al. generated knock-in mice that carry mutations in the Pdgfra (platelet-derived growth-factor-receptor- alpha ) gene, which selectively prevent this RTK from activating two of its target signalling proteins, PI3 kinase and Src kinase. Their findings show that loss of PI3 kinase activation leads to neonatal lethality due to impaired signalling in many cell types, whereas loss of Src activation affects only oligodendrocyte development.

Kidney Disease

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A chemokine receptor CCR-1 antagonist reduces renal fibrosis after unilateral ureter ligation
Anders, H.-J. et al. J. Clin. Invest. 109, 251–259 (2002) [PubMed]

In the kidney, tubulointerstitial fibrosis is the main predictor for the progression to end-stage renal failure. Expression of chemokines and their receptors is thought to contribute to leukocyte infiltration and fibrosis after unilateral ureter obstruction (UUO). In a mouse model, nonpeptide antagonists of the chemokine receptor CCR1 could reduce leukocyte infiltration and fibrosis after UUO. Markers of renal fibrosis were all significantly reduced by CCR1-antagonist treatment compared with controls. CCR1 blockade could represent a new therapeutic strategy for reducing cellular infiltration and fibrosis as principal factors in the progression to renal failure.

Mouse Models

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Genetic analysis of Pten and Ink4a/Arf interactions in the suppression of tumorigenesis in mice.
You, M. J. et al. Proc. Natl Acad. Sci. USA 99, 1455–1460 (2002) [PubMed]

CDKN2A — which encodes transcripts of the tumour-suppressor proteins INK4A and ARF — and PTEN are frequently mutated in human cancer, but do they cooperate in tumorigenesis? Cdkn2a ^-/- Pten ^+/- mouse embryonic fibroblasts that are grown in low serum show higher proliferation rates than Cdkn2a ^-/- Pten ^+/+ cells, and Cdkn2a ^-/- Pten ^+/– mice are also more tumour prone and succumb to an increased range of tumour types. The two tumour-suppressor genes therefore seem to cooperate to prevent tumour formation.

T-cell Development

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Tox: an HMG box protein implicated in the regulation of thymocyte selection.
Wilkinson, B. et al. Nature Immunol. 3, 272–280 (2002) [ PubMed ]

T-cell receptor (TCR) signalling is vital for the positive selection of mature T cells. How these signals are translated into changes in gene expression that are required for T-cell maturation and lineage commitment is unknown. This study describes the identification of Tox, which encodes an high mobility group (HMG) box family DNA-binding protein. Tox mRNA and protein are upregulated in T cells undergoing positive selection, and Tox transgenic mice have increased CD8⁺ and reduced CD4⁺ thymocytes. This perturbed lineage commitment might result from Tox-mediated changes in gene expression.

Lymphocyte Migration

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CXCL13 is required for B1-cell homing, natural antibody production and body cavity immunity.
Ansel, K. M., Harris, R. B. & Cyster, J. G. Immunity 16, 67–76 (2002) [ PubMed ]

B1 cells predominate in the body cavities and participate in innate defence by producing natural antibody. Here the authors show that the chemokine CXCL13, which is essential for the homing of conventional (B2) B cells to B-cell follicles, is also crucial for the homing of B1 B cells to the peritoneum. CXCL13^-/- mice lack peritoneal B1 cells and have reduced levels of natural antibody, as well as dimininshed responses to classic B1-cell ligands, such as phosphorylcholine. Two key sources of CXCL13 were identified — peritoneal macrophages and stromal cells within the omentum.