Glenn D. Rosen

Diversity of gene expression in adenocarcinoma of the lung.

The global gene expression profiles for 67 human lung tumors representing 56 patients were examined by using 24,000-element cDNA microarrays. Subdivision of the tumors based on gene expression patterns faithfully recapitulated morphological classification of the tumors into squamous, large cell, small cell, and adenocarcinoma. The gene expression patterns made possible the subclassification of adenocarcinoma into subgroups that correlated with the degree of tumor differentiation as well as patient survival. Gene expression analysis thus promises to extend and refine standard pathologic analysis.

Roles for the integrin VLA-4 and its counter receptor VCAM-1 in myogenesis

Mammalian myogenesis is biphasic: primary myoblasts fuse to form primary myotubes, then secondary myoblasts align along the primary myotubes and form secondary myotubes, which comprise most of adult muscle. We provide evidence that an integrin (VLA-4) and its counter receptor (VCAM-1) have a role in secondary myogenesis. Both receptors are synthesized by cultured muscle cells: VLA-4 is induced as myotubes form, whereas VCAM-1 is present on myoblasts and myotubes. In vivo, both molecules are expressed at sites of secondary myogenesis, VLA-4 on primary and secondary myotubes, and VCAM-1 on secondary myoblasts and on regions of secondary myotubes apposed to primary myotubes. These patterns suggest that VLA-4-VCAM-1 interactions influence alignment of secondary myoblasts along primary myotubes and/or the fusion of secondary myoblasts. In support of the latter possibility, antibodies to VLA-4 or VCAM-1 inhibit myotube formation in culture.

Cleavage of Focal Adhesion Kinase by Caspases during Apoptosis

Apoptotic cells undergo characteristic morphological changes that include detachment of cell attachment from the substratum and loss of cell-cell interactions. Attachment of cells to the extracellular matrix and to other cells is mediated by integrins. The interactions of integrins with the extracellular matrix activates focal adhesion kinase (FAK) and suppresses apoptosis in diverse cell types. Members of the tumor necrosis family such as Fas and Apo-2L, also known as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), induce apoptosis in both suspension and adherent cells through the activation of caspases. These caspases, when activated, cleave substrates that are important for the maintenance of nuclear and membrane integrity. In this study, we show that FAK is sequentially cleaved into two different fragments early in Apo-2L-induced apoptosis. We also demonstrate that FAK cleavage is mediated by caspases and that FAK shows unique sensitivity to different caspases. Our results suggest that disruption of FAK may contribute to the morphological changes observed in apoptotic suspension and adherent cells.

The nature and identification of quantitative trait loci: a community’s view

This white paper by eighty members of the Complex Trait Consortium presents a communitys view on the approaches and statistical analyses that are needed for the identification of genetic loci that determine quantitative traits. Quantitative trait loci (QTLs) can be identified in several ways, but is there a definitive test of whether a candidate locus actually corresponds to a specific QTL?

Planum temporale asymmetry, reappraisal since Geschwind and Levitsky

Abstract This study utilizes the same brains reported by Geschwind and Levitsky [Science161, 186–187, 1968] and looks for indirect evidence for the Geschwind Hypothesis [Geschwind and Bahan, Proc. natn. Acad Sci., U.S.A.79, 5097–5100, 1982; Geschwind and Galaburda, Arch. Neurol.42, 428–459, 521–552, 634–654, 1985] that testosterone slows down the development of the left hemisphere and allows for compensatory growth of the right in order to produce a graded shift away from standard cerebral asymmetry. There are graded asymmetries of the planum temporal in the population, averaging on the side of leftward asymmetry. Changes away from asymmetry, however, involve increase in the size of the smaller side, rather than decrease in the size of the larger. Thus symmetrical brains differ from asymmetrical brains by having two large plana, each planum being equivalent in area to the larger planum of the asymmetrical cases. If testosterone has an effect in modifying brain asymmetry, it does not appear to do so by slowing one side and allowing the growth of the other, but rather through its promotion of the growth of the small side. We consider some likely developmental mechanisms for this action and offer some anatomical and functional comments.

From genes to behavior in developmental dyslexia

All four genes thus far linked to developmental dyslexia participate in brain development, and abnormalities in brain development are increasingly reported in dyslexia. Comparable abnormalities induced in young rodent brains cause auditory and cognitive deficits, underscoring the potential relevance of these brain changes to dyslexia. Our perspective on dyslexia is that some of the brain changes cause phonological processing abnormalities as well as auditory processing abnormalities; the latter, we speculate, resolve in a proportion of individuals during development, but contribute early on to the phonological disorder in dyslexia. Thus, we propose a tentative pathway between a genetic effect, developmental brain changes, and perceptual and cognitive deficits associated with dyslexia.

INDIVIDUAL VARIABILITY IN CORTICAL ORGANIZATION: ITS RELATIONSHIP TO BRAIN LATERALITY AND IMPLICATIONS TO FUNCTION

The human brain and the brains of most mammals studied for this purpose demonstrate hemispheric asymmetry of gross anatomical landmarks and/or architectonic cortical subdivisions. The magnitude as well as the direction of these cortical asymmetries vary among individuals, and in some species there exist significant population directional biases. The magnitude, if not the direction, of cortical asymmetry is found to predict for relative numbers of neurons comprising a given pair of hemispheric architectonic homologues such that the more asymmetric the region is, the smaller the number of neurons. Similarly, the more asymmetric a region is, the smaller the density of interhemispheric connections and (probably) the greater the density of intrahemispheric connections. Developmentally, the decrease in the number of neurons characterizing the more asymmetrical regions appears to reflect mainly increased unilateral ontogenetic cell loss, and diminished callosal connectivity might signify increased developmental axonal pruning. These relationships between cell numbers, callosal connections, and presumed intrahemispheric relationships can be entertained to explain variability in anatomo-clinical correlations for language function and aphasia between left- and right-handers and men and women.

PG490 (triptolide) cooperates with tumor necrosis factor-alpha to induce apoptosis in tumor cells.

Progress in the treatment of solid tumors has been slow and sporadic. The efficacy of conventional chemotherapy in solid tumors is limited because tumors frequently have mutations in the p53 gene. Also, chemotherapy only kills rapidly dividing cells. Members of the tumor necrosis factor (TNF) family, however, induce apoptosis regardless of the p53 phenotype. Unfortunately, the cytotoxicity of TNF-α is limited by its activation of NF-κB and activation of NF-κB is proinflammatory. We have identified a compound called PG490, that is composed of purified triptolide, which induces apoptosis in tumor cells and sensitizes tumor cells to TNF-α-induced apoptosis. PG490 potently inhibited TNF-α-induced activation of NF-κB. PG490 also blocked TNF-α-mediated induction of c-IAP2 (hiap-1) and c-IAP1 (hiap-2), members of the inhibitor of apoptosis (IAP) family. Interestingly, PG490 did not block DNA binding of NF-κB, but it blocked transactivation of NF-κB. Our identification of a compound that blocks TNF-α-induced activation of NF-κB may enhance the cytotoxicity of TNF-α on tumors in vivo and limit its proinflammatory effects.

BRAIN AND BEHAVIORAL ASYMMETRIES FOR SPATIAL PREFERENCE IN RATS

Rats were handled daily for 3 min between birth and weaning, or were nonhandled controls. When adult, 4 males from each litter received a right neocortical ablation, a left ablation, a sham operation, or no surgery. A month later all animals were tested in the open field for 4 days, and their initial direction of movement from the starting square (whether right or left) was recorded. Non-handled rats with intact brains (sham-operated and no-surgery groups pooled) had a mean directionality score near zero, thus indicating no right-left spatial preference. However, non-handled animals without a left hemisphere were significantly more biased in going to the ipsilateral side than were their siblings with right-brain ablations. Thus, in non-handled animals behavioral symmetry in making spatial choices is due to balanced brain asymmetry, in which the right hemisphere biases the animal to move leftward while the left hemisphere acts to inhibit this response. In contrast, intact handled rats had a significant preference to go to the left, thus suggesting that in handled animals the right hemisphere controls spatial preference.

Dexamethasone inhibits lung epithelial cell apoptosis induced by IFN-γ and Fas

Lung epithelium plays a central role in modulation of the inflammatory response and in lung repair. Airway epithelial cells are targets in asthma, viral infection, acute lung injury, and fibrotic lung disease. Activated T lymphocytes release cytokines such as interferon-γ (IFN-γ) that can cooperate with apoptotic signaling pathways such as the Fas-APO-1 pathway to induce apoptosis of damaged epithelial cells. We report that IFN-γ alone and in combination with activation of the Fas pathway induced apoptosis in A549 lung epithelial cells. Interestingly, the corticosteroid dexamethasone was the most potent inhibitor of IFN-γ- and IFN-γ plus anti-Fas-induced apoptosis. IFN-γ induced expression of an effector of apoptosis, the cysteine protease interleukin-1β-converting enzyme, in A549 cells. Dexamethasone, in contrast, induced expression of an inhibitor of apoptosis, human inhibitor of apoptosis (hIAP-1), also known as cIAP2. We suggest that the inhibition of epithelial cell apoptosis by corticosteroids may be one mechanism by which they suppress the inflammatory response.