How distinct stem cell populations originate and whether there is a clear stem cell "genetic signature" remain poorly understood. Understanding the evolution of stem cells requires molecular profiling of stem cells in an animal at a basal phylogenetic position. In this study, using transgenic Hydra polyps, we reveal for each of the three stem cell populations a specific signature set of transcriptions factors and of genes playing key roles in cell type-specific function and interlineage communication. Our data show that principal functions of stem cell genes, such as maintenance of stemness and control of stem cell self-renewal and differentiation, arose very early in metazoan evolution. They are corroborating the view that stem cell types shared common, multifunctional ancestors, which achieved complexity through a stepwise segregation of function in daughter cells.

Hydra ’s unlimited life span has long attracted attention from natural scientists. The reason for that phenomenon is the indefinite self-renewal capacity of its stem cells. The underlying molecular mechanisms have yet to be explored. Here, by comparing the transcriptomes of Hydra ’s stem cells followed by functional analysis using transgenic polyps, we identified the transcription factor forkhead box O (FoxO) as one of the critical drivers of this continuous self-renewal. foxO overexpression increased interstitial stem cell and progenitor cell proliferation and activated stem cell genes in terminally differentiated somatic cells. foxO down-regulation led to an increase in the number of terminally differentiated cells, resulting in a drastically reduced population growth rate. In addition, it caused down-regulation of stem cell genes and antimicrobial peptide (AMP) expression. These findings contribute to a molecular understanding of Hydra ’s immortality, indicate an evolutionarily conserved role of FoxO in controlling longevity from Hydra to humans, and have implications for understanding cellular aging.

The phospholipase neutral sphingomyelinase (N-SMase) has been recognized as a major mediator of processes such as inflammation, development and growth, differentiation and death of cells, as well as in diseases such as Alzheimer's, atherosclerosis, heart failure, ischemia/reperfusion damage, or combined pituitary hormone deficiency. Although activation of N-SMase by the proinflammatory cytokine TNF was described almost two decades ago, the underlying signaling pathway is unresolved. Here, we identify the Polycomb group protein EED (embryonic ectodermal development) as an interaction partner of nSMase2. In yeast, the N terminus of EED binds to the catalytic domain of nSMase2 as well as to RACK1, a protein that modulates the activation of nSMase2 by TNF in concert with the TNF receptor 1 (TNF-R1)-associated protein FAN. In mammalian cells, TNF causes endogenous EED to translocate from the nucleus and to colocalize and physically interact with both endogenous nSMase2 and RACK1. As a consequence, EED and nSMase2 are recruited to the TNF-R1•FAN•RACK1-complex in a timeframe concurrent with activation of nSMase2. After knockdown of EED by RNA interference, the TNF-dependent activation of nSMase2 is completely abrogated, identifying EED as a protein that both physically and functionally couples TNF-R1 to nSMase2, and which therefore represents the "missing link" that completes one of the last unresolved signaling pathways of TNF-R1.embryonic ectodermal development | immune response | inflammation N eutral sphingomyelinases (N-SMases) mediate stress-induced ceramide generation and participate in inflammation, development, cellular growth, differentiation and death, heart failure, ischemia/reperfusion damage, atherosclerosis, and Alzheimer's disease (1, 2). They are acutely activated by TNF, a major mediator of inflammatory and immunoregulatory responses (3, 4). Out of the three N-SMase genes cloned in mammals, nSMase2 corresponds to the biochemically characterized N-SMase. It is a membrane-bound protein with two putative N-terminal hydrophobic membrane-anchoring domains, a collagen-like linker region, and a C-terminal catalytic domain (Fig. 1A) (5). nSMase2 has been linked to cell cycle regulation and contact inhibition (1), late embryonal and postnatal development (5, 6), exosome secretion (7), and Alzheimer's disease and combined pituitary hormone deficiency (1, 6). In response to TNF, nSMase2 is important for inflammatory signaling, cell adhesion and migration, endothelial regulation, cell death, and cutaneous barrier repair (5,(8)(9)(10)(11). Even though N-SMase activation by TNF has been reported since almost 20 years ago (3), the corresponding signaling pathway is not fully resolved. In response to TNF, nSMase2 is activated exclusively by the 55-kDa receptor TNF receptor 1 (TNF-R1) (10). We have previously defined a neutral sphingomyelinase activation domain (NSD) within TNF-R1 (12) that serves as a binding site for the protein FAN (factor associated with N-SMase activation) (13). FAN recruits the WD repeat protein...

The chemokine SDF-1/CXCL12 induces and modulates major steps of ontogenesis, regeneration and tumorigenesis. Depending on the organ or tissue, CXCL12 serves as a proliferation or cell survival factor, influences differentiation, induces adhesion and/or regulates cell migration. These functions are mediated by the two chemokine receptors, CXCR4 and CXCR7. Whereas CXCR4 is still viewed as the sole G-protein-activating and, hence, signaling receptor for CXCL12, CXCR7 is regarded as a non-classic scavenging or decoy receptor that modulates the function of CXCR4. However, this view might be too limited, since evidence has accumulated favoring a cell-type-specific mode of CXCL12 signaling. In addition to the "classic" CXCL12 signaling mode via CXCR4, CXCR4 and CXCR7 have to form a receptor unit for successful CXCL12 signaling in some cells. Moreover, examples exist whereby CXCL12 receptors split functions or switch roles, such that CXCR7 (instead of CXCR4) mediates signal transduction. The obvious lack of a universal mode of CXCL12 signaling urges a re-evaluation of the role of this chemokine in development, health and disease. This review depicts the exceptional characteristics of CXCL12-induced signal transduction in various cells and organs, points out remaining controversies and mentions consequences for therapeutic interventions.

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The present study shows that the CXCR4/SDF-1 axis regulates the migration of second branchial archderived muscles as well as non-somitic neck muscles. Cxcr4 is expressed by skeletal muscle progenitor cells in the second branchial arch (BA2). Muscles derived from the second branchial arch, but not from the first, fail to form in Cxcr4 mutants at embryonic days E13.5 and E14.5. Cxcr4 is also required for the development of non-somitic neck muscles. in Cxcr4 mutants, non-somitic neck muscle development is severely perturbed. In vivo experiments in chicken by means of loss-of-function approach based on the application of beads loaded with the CXCR4 inhibitor AMD3100 into the cranial paraxial mesoderm resulted in decreased expression of Tbx1 in the BA2. Furthermore, disrupting this chemokine signal at a later stage by implanting these beads into the BA2 caused a reduction in MyoR, Myf5 and MyoD expression. In contrast, gain-of-function experiments based on the implantation of SDF-1 beads into BA2 resulted in an attraction of myogenic progenitor cells, which was reflected in an expansion of the expression domain of these myogenic markers towards the SDF-1 source. Thus, Cxcr4 is required for the formation of the BA2 derived muscles and non-somitic neck muscles.In vertebrates, trunk muscles originate from the somites, whereas most of the head muscles originate from the cranial paraxial mesoderm (CPM) 1,2 . Neck muscle progenitor cells are found in the transition zone between somite and CPM 3,4 . The CPM cells transiently migrate laterally into the region of the branchial arches and contributes to the muscles of the head 5,6 . These muscles can be divided into branchial, extra-ocular (EOM), axial and laryngoglossal muscles 2 . BAs are made of surface ectoderm, endoderm, myogenic mesodermal cells and neural crest cells (NCCs) 7 . The BA1 mesoderm contributes to formation of mastication muscles. The BA2 mesoderm gives rise to facial expression muscles 8 . Skeletal muscle progenitor cells in the more caudal BAs (3rd, 4th and 6th) are thought to contribute to neck muscles, for example the trapezius and sternocleidomastoideus, or its birds homologue the cucullaris muscle 3,4 . Clonal analysis reports that trapezius and sternocleidomastoid neck muscles are formed from non-somitic progenitor cells, whereas splenius muscle and laryngeal muscles have a dual origin (somitic and non-somitic) of the progenitor cells 3,4 . The genetic regulation of craniofacial myogenesis remains to be fully elucidated 5,8-10 .The signaling cascades that control pre-myogenic progenitor cell specification act distinctly in the head and trunk muscles 1,8 . Several pre-myogenic genes that are required to initiate myogenesis and maintain cells in an immature state in the trunk are known. Pax3, Pax7 and Lbx1 are crucial in specifying pre-myogenic progenitor cells in the dermomyotomes, the parts of the somites that gives rise to trunk and limb myoblasts 8,11 . The expression of Pax3 and Pax7 in somites is normally downregulated before activation of Myogenin...

The chemokine, CXCL12, promotes cancer growth and metastasis through interaction with either CXCR4 and/or CXCR7. This tumor-specific organization of the CXCL12 system obscures current therapeutic approaches, aiming at the selective inactivation of CXCL12 receptors. Since it has been previously suggested that the cellular use of CXCR4 or CXCR7 is dictated by the 5T4 oncofetal glycoprotein, we have now tested whether 5T4 would represent a general and reliable marker for the organization of the CXCL12 system in cancer cells. The CXCR4 antagonist, AMD3100, as well as the CXCR7 antagonist, CCX771, demonstrated that the cancer cell lines A549, C33A, DLD-1, MDA-231, and PC-3 use either CXCR7 and/or CXCR4 for mediating CXCL12-induced chemotaxis and cell proliferation. The use of CXCL12 receptors as well as their subcellular localization remained unchanged in most cell lines following siRNA-mediated depletion of 5T4. In distinct cell lines, inhibition of 5T4 expression, however, modulated tumor cell migration and proliferation per se. Collectively our analyses fail to demonstrate general organizational influences of 5T4 of the CXCL12 system in different cancer cell lines, and, hence, dismiss its future use as a diagnostic marker.