LifeMap Discovery™ provides investigators with an integrated database of embryonic development, stem cell biology and regenerative medicine. The hand-curated reconstruction of cell ontology with stem cell biology; including molecular, cellular, anatomical and disease-related information, provides efficient and easy-to-use, searchable research tools. The database collates in vivo and in vitro gene expression and guides translation from in vitro data to the clinical utility, and thus can be utilized as a powerful tool for research and discovery in stem cell biology, developmental biology, disease mechanisms and therapeutic discovery. LifeMap Discovery is freely available to academic nonprofit institutions at http://discovery.lifemapsc.com

Michael Bustin, bustin@helix.nih.gov Directed cell migration is a property central to multiple basic biological processes. Here, we show that directed cell migration is associated with global changes in the chromatin fiber. Polarized posttranslational changes in histone H1 along with a transient decrease in H1 mobility were detected in cells facing the scratch in a wound healing assay. In parallel to the changes in H1, the levels of the heterochromatin marker histone H3 lysine 9 trimethylation were elevated. Interestingly, reduction of the chromatin-binding affinity of H1 altered the cell migration rates. Moreover, migration-associated changes in histone H1 were observed during nuclear motility in the simple multicellular organism Neurospora crassa. Our studies suggest that dynamic reorganization of the chromatin fiber is an early event in the cellular response to migration cues. Directed cell migration is a fundamental property of both simple and complex organisms, which is necessary for the proper execution of various biological processes including foraging, embryonic development, immunity, tissue repair and homeostasis. Improper cell migration is an underlying cause of numerous pathological conditions such as vascular diseases, chronic inflammatory diseases, cancer and cognitive disorders. Induction of directed cell migration results in cellular polarization, a process that involves dynamic changes in the actin cytoskeleton and in the adhesion molecules. In parallel, the microtubule-organizing center and the Golgi apparatus are reoriented (1,2) through nuclear movement (3). The nuclei of migrating cells display a wide range of structural changes. Developmentally related nuclear polarization has been noted in the single cell algae Chlamydomonas, where nuclear pore complexes localize to the posterior side of the nucleus and heterochromatin to the anterior side of the nucleus (4). Cancer cells change their nuclear shape and assume an elongated structure in capillaries (5). Migrating neurons change the structure of the nucleus during migration in a prototypic fashion (6,7). These types of morphological changes of the cell nucleus raise the possibility that cell migration is associated with the reorganization of the chromatin fiber. This possibility, which has obvious functional consequences, has not been investigated in detail yet.To monitor possible chromatin structural changes, we focused on histone H1, one of the most abundant and ubiquitous families of chromatin-binding proteins. H1 molecules are involved in diverse nuclear processes, and their intranuclear organization is affected by various cellular conditions and stimuli (8,9). We now show that following migration cues, the mobility of histone H1 is decreased in correlation with increased level of the heterochromatin marker histone H3 lysine 9 tri-methylation (H3K9me3). Altered properties of linker histone in migrating nuclei are evolutionary conserved and were also found in the fungus Neurospora crassa. Furthermore, alterations in the interaction of H1 wi...

Platelet-activating factor acetylhydrolase 1B (PAF-AH) inactivates the potent phospholipid platelet-activating factor (PAF) and is composed of two catalytic subunits (α1 and α2) and a dimeric regulatory subunit, LIS1. The function of the catalytic subunits in brain development remains unknown. Here we examined their effects on proliferation in the ganglionic eminences and tangential migration. In α1 and α2 catalytic subunits knockout mice we noticed an increase in the size of the ganglionic eminences resulting from increased proliferation of GABAergic neurons. Our results indicate that the catalytic subunits act as negative regulators of the Wnt signaling pathway. Overexpression of each of the PAF-AH catalytic subunits reduced the amount of nuclear beta-catenin and provoked a shift of this protein from the nucleus to the cytoplasm. In the double mutant mice, Wnt signaling increased in the ganglionic eminences and in the dorsal part of the cerebral cortex. In situ hybridization revealed increased and expanded expression of a downstream target of the Wnt pathway (Cyclin D1), and of upstream Wnt components (Tcf4, Tcf3 and Wnt7B). Furthermore, the interneurons in the cerebral cortex were more numerous and in a more advanced position. Transplantation assays revealed a non-cell autonomous component to this phenotype, which may be explained in part by increased and expanded expression of Sdf1 and Netrin-1. Our findings strongly suggest that PAF-AH catalytic subunits modulate the Wnt pathway in restricted areas of the developing cerebral cortex. We hypothesize that modulation of the Wnt pathway is the evolutionary conserved activity of the PAF-AH catalytic subunits.

Stem cells exhibit a promiscuous gene expression pattern.We show herein that the early embryo and adult MSCs express B-cell receptor component mRNAs. To examine possible bearings of these genes on the expressing cells, we studied immunoglobulin chain-deficient mice. Pregnant chain-deficient females were found to produce a higher percentage of defective morulae compared with control females. Structure analysis indicated that the mRNA species found in embryos and in mesenchyme consist of the constant region of the heavy chain that encodes a recombinant 50-kDa protein. In situ hybridization localized the constant gene expression to loose mesenchymal tissues within the day-12.5 embryo proper and the yolk sac. In early embryo and in adult mesenchyme from -deficient mice, ␦ replaced chain, implying a possible requirement of these alternative molecules for embryo development and mesenchymal functions. Indeed, overexpression of the mesenchymal-truncated heavy chain in 293T cells resulted in specific subcellular localization and in G 1 growth arrest. The lack of such occurrence following overexpression of a complete, rearranged form of chain suggests that the mesenchymal version of this mRNA may possess unique functions. STEM CELLS 2007; 25:761-770

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