The use of embryonic stem (ES) cells for generating healthy tissues has the potential to revolutionize therapies for human disease or injury, for which there are currently no effective treatments. Strategies for manipulating stem cell differentiation should be based on knowledge of the mechanisms by which lineage decisions are made during early embryogenesis. Here, we review current research into the factors influencing lineage differentiation in the mouse embryo and the application of this knowledge to in vitro differentiation of ES cells. In the mouse embryo, specification of tissue lineages requires cell-cell interactions that are influenced by coordinated cell migration and cellular neighborhood mediated by the key WNT, FGF, and TGFbeta signaling pathways. Mimicking the cellular interactions of the embryo by providing appropriate signaling molecules in culture has enabled the differentiation of ES cells to be directed predominately toward particular lineages. Multistep strategies incorporating the provision of soluble factors known to influence lineage choices in the embryo, coculture with other cells or tissues, genetic modification, and selection for desirable cell types have allowed the production of ES cell derivatives that produce beneficial effects in animal models. Increasing the efficiency of this process can only result from a better understanding of the molecular control of cell lineage determination in the embryo.
CCN2/Connective Tissue Growth Factor (CTGF) is a matricellular protein that regulates cell adhesion, migration, and survival. CCN2 is best known for its ability to promote fibrosis by mediating the ability of transforming growth factor β (TGFβ) to induce excess extracellular matrix production. In addition to its role in pathological processes, CCN2 is required for chondrogenesis. CCN2 is also highly expressed during development in endothelial cells, suggesting a role in angiogenesis. The potential role of CCN2 in angiogenesis is unclear, however, as both pro- and anti-angiogenic effects have been reported. Here, through analysis of Ccn2-deficient mice, we show that CCN2 is required for stable association and retention of pericytes by endothelial cells. PDGF signaling and the establishment of the endothelial basement membrane are required for pericytes recruitment and retention. CCN2 induced PDGF-B expression in endothelial cells, and potentiated PDGF-B-mediated Akt signaling in mural (vascular smooth muscle/pericyte) cells. In addition, CCN2 induced the production of endothelial basement membrane components in vitro, and was required for their expression in vivo. Overall, these results highlight CCN2 as an essential mediator of vascular remodeling by regulating endothelial-pericyte interactions. Although most studies of CCN2 function have focused on effects of CCN2 overexpression on the interstitial extracellular matrix, the results presented here show that CCN2 is required for the normal production of vascular basement membranes.
Cellulase, polygalacturonase (PG), pectinmethylesterase (PME), respiration, and ethylene production were determined in single "Fuerte" avocado fruits from the day of harvest through the start of fruit breakdown. PME declined from its maximum value at the time of picking to a low level early in the climacteric. PG activity was not detectable in the preclimacteric stage, increased during the climacteric, and continued to increase during the postclimacteric phase to a level three times greater than when the fruit reached the edible soft stage. Celulase activity was low in the preclimacteric fruit, started to increase just as respiration increased, and reached a level two times greater than at the edible soft stage. Cellulase activity started to increase 3 days before PG activity could be detected. Increased production of ethylene foUlowed the increase in respiration and ceUulase activity by about 1.5 days. These results indicate that a close relation exists between the rapid increase in the ceOl waUl-depolymerizing enzymes and the rise in respiration and ethylene production and refocused attention on the role of the cell wail and the associated plasma membrane in the early events of fruit ripening.The avocado fruit starts to ripen only after being detached from the tree. After harvest, the most obvious ripening change is the rapid transition of the mesocarp from a hard to a soft, butter-like consistency with an apparent total loss of structural integrity.Several researchers have studied the relation between softening of the avocado fruit and the activity of cell wall-degrading enzymes. Lewis et al. (17) were the first to note that the hard avocado mesocarp presented barely detectable levels of cellulase activity whereas the activity in soft fruit was highest ever observed in plant tissues. Pesis et al. (20) found a direct correlation between cellulase activity, softening, respiration, and ethylene production. Awad (2) also found a close relation between the rapid increase in cellulase content after harvest, the climacteric rise in respiration, and softening of the fruit. He determined that edible softness occurred before maximum cellulase levels were reached.Raymond and Phaff (21) first showed a positive relationship between PG activity and softening of the avocado fruit. Later, Barash and Khazzam (3) and Zauberman and Schiffmann-Nadel (24) found that PG3 activity increased rapidly after harvest.The postharvest decrease in PME activity in the avocado fruit 'Research Fellow, CNPq, Brazil. (9), and Barmore and Rouse (4). We lack, however, precise information on the simultaneous variaton of these three enzymes as well as their relation to respiration, ethylene production, and softening of the fruit. Since there is considerable variation in the time of ripening of individual fruit, we show here the changes in three enzymes in relation to respiration and ethylene production in single fruit. MATERIALS AND METHODSMeasurement of Respiration and Ethylene Production. "Fuerte" avocado fruits were placed in glass ja...
Loss of Dkk1 results in ectopic WNT/β-catenin signalling activity in the anterior germ layer tissues and impairs cell movement in the endoderm of the mouse gastrula. The juxtaposition of the expression domains of Dkk1 and Wnt3 is suggestive of an antagonistagonist interaction. The downregulation of Dkk1 when Wnt3 activity is reduced reveals a feedback mechanism for regulating WNT signalling. Compound Dkk1;Wnt3 heterozygous mutant embryos display head truncation and trunk malformation, which are not found in either Dkk1 +/-or Wnt3 +/-embryos. Reducing the dose of Wnt3 gene in Dkk1 -/-embryos partially rescues the truncated head phenotype. These findings highlight that head development is sensitive to the level of WNT3 signalling and that DKK1 is the key antagonist that modulates WNT3 activity during anterior morphogenesis.
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