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DIR Papers of the Month

By Eddy Ball
May 2007

Receptor Signaling Key in Mouse Embryo Development

NIEHS-funded investigators have demonstrated in vivo the crucial role played by a bone morphogenetic protein (BMP) type I receptor known as ALK2 in early mouse embryogenesis. The scientists from the NIEHS Molecular Developmental Biology Group and the Knock Out Core, in collaboration with two University of Southern California researchers, reported their results in the February issue of the journal Developmental Dynamics.

The research team analyzed mutant mice embryos with deleted gene coding sequences, called exons, to determine the effects on development. A normal vertebrate embryo develops from a simple multi-cell state (blastocyst) into a complex, three-dimensional organism through an infolding process called gastrulation. The investigators found that mutation in Alk2 by deletion of exon 5 or 7 interfered with BMP signaling and prevented gastrulation from taking place. The embryo died as a result of failing to undergo normal development. Expression analyses identified dramatic down-regulation of key genes for proper development, suggesting that Alk2 is involved in their cascades.

While the downstream target genes of Alk2 are as yet unknown, this study brings researchers closer to understanding the causes of developmental failure in the mouse embryo - and offers insight into developmental problems, such as cranial, cardiac and neuronal dysgenesis in human and other mammalian embryo.

Citation: Komatsu Y, Scott G, Nagy A, Kaartinen V, Mishina Y( Exit NIEHS. 2007. BMP type I receptor ALK2 is essential for proper patterning at late gastrulation during mouse embryogenesis. Dev Dyn 236(2):512-517.

Receptor D6-Deficient Mice Show Lowered Airway Reactivity

In a recent NIEHS-funded study, a team of researchers led by investigators in the Laboratory of Respiratory Biology found an unexpected decrease in airway reactivity among allergen-challenged receptor D6-deficient mice. The researchers had set out to determine whether D6 has chemokine-binding and anti-inflammatory functions in the lung, as it does in the skin.

To do this, the researchers compared the responses of D6-deficient mice and genetically matched C57BL/6 mice that had been sensitized to ovalbumin and exposed to either a single-day acute or a 7-day challenge with this allergen. The investigators then analyzed airway inflammation and chemokine levels, leukocyte accumulation and airway responsiveness. They found that the D6-deficient mice had greater pulmonary inflammation than C57BL/6 mice following these challenges. Unexpectedly, however, they found that airway responses after the acute exposure were significantly higher in C57BL/6 mice than in the D6-deficient strain, despite the higher levels of inflammation in the altered strain. The same trend was also seen in naïve D6-deficient mice.

If it can be determined that D6 functions similarly in humans, the researchers concluded, "antagonists of D6 might provide a novel therapeutic avenue to reduce air hyper-reactivity in some clinical settings."

Citation: Whitehead GS, Wang T, DeGraff LM, Card JW, Lira SA, Graham GJ, Cook DN( Exit NIEHS. 2007. The chemokine receptor D6 has opposing effects on allergic inflammation and airway reactivity. Am J Respir Crit Care Med 175(3):243-249.

Inflammation Pathways and the Blood-Brain Barrier

Researchers at the NIEHS Laboratory of Pharmacology and Chemistry have described a novel signaling pathway that, when activated by chronic inflammation, can up-regulate a drug efflux transport protein that tightens the blood brain barrier protecting the central nervous system (CNS). For a significant number of patients, this tightening of the barrier effectively reduces the efficacy of pharmacological treatment for such CNS disorders as epilepsy and gliobastoma, a common primary tumor of the brain.

The researchers examined the long term consequences of inflammation by continuously exposing rat brain capillaries in vitro to one of two inflammatory mediators, tumor necrosis factor-α or endothelin-1, components of the brain's innate immune response. Exposure triggered a rapid, initial decrease in P-glycoprotein activity, two- to three-hours at the low activity level and then a dramatic increase in activity. The initial weakening of the barrier's selective defense may provide a therapeutic window for pharmaceuticals that normally enter the CNS poorly. The dramatic up-regulation of P-glycoprotein activity six hours following the brain's initial immune response then makes it harder for drugs to reach the CNS.

Results of the study, which appeared in the March 2007 issue of the journal Molecular Pharmacology, may point the way toward development of new interventions to treat CNS disorders, possibly by targeting inflammatory signaling pathway the authors were the first investigators to describe.

Citation: Bauer B, Hartz AM, Miller DS( Exit NIEHS. 2007.Tumor necrosis factor alpha and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier. Mol Pharmacol 71(3):667-675.

Smoking Linked to Increased Telomerase Activity in Lung Cells

A multi-disciplinary research team has demonstrated a strong association between levels of telomerase activity and the number of pack-years of smoking in human cell culture analysis. Telomerase is an enzyme that regulates cell replication, and increases in telomerase activity may signal the development of cancerous cells.

The NIEHS-funded team included investigators from the Laboratory of Molecular Carcinogenesis, Epidemiology Branch and Biostatistics Branch working in collaboration with scientists from the Catholic University of Korea, Vanderbilt University and the University of North Carolina at Chapel Hill. The scientists obtained bronchial epithelial (HBE) cells from 26 subjects and determined the telomerase activity in the cultures using a telomeric repeat amplification protocol assay.

The study could not establish definitively a causative role of tobacco in the activation of telomerase. However, the research team did demonstrate an association between tobacco carcinogen exposure and telomerase activity in normal bronchial epithelium - suggesting that tobacco carcinogen exposure might reflect an early and specific molecular change that is associated with an increased potential lifespan of these cells.

This research is important because telomerase activation and other epigenetic alterations, such as K-ras activation, p16 promoter hyper-methylation and p53 mutation, can occur in normal human cells before any clinical evidence of the disease is manifest.

Citation: Yim HW, Slebos RJ, Randell SH, Umbach DM, Parsons AM, Rivera MP, Detterbeck FC, Taylor JA( Exit NIEHS. 2007. Smoking is associated with increased telomerase activity in short-term cultures of human bronchial epithelial cells. Cancer Lett 246(1-2):24-33.

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