The Core Protein of Glypican Daily-Like Determines Its Biphasic Activity in Wingless Morphogen Signaling

Dally-like (Dlp) is a glypican-type heparan sulfate proteoglycan (HSPG), containing a protein core and attached glycosaminoglycan (GAG) chains. In Drosophila wing discs, Dlp represses short-range Wingless (Wg) signaling, but activates long-range Wg signaling. Here, we show that Dlp core protein has similar biphasic activity as wild-type Dlp. Dlp core protein can interact with Wg; the GAG chains enhance this interaction. Importantly, we find that Dlp exhibits a biphasic response, regardless of whether its glycosylphosphatidylinositol linkage to the membrane can be cleaved. Rather, the transition from signaling activator to repressor is determined by the relative expression levels of Dlp and the Wg receptor, Frizzled (Fz) 2. Based on these data, we propose that the principal function of Dlp is to retain Wg on the cell surface. As such, it can either compete with the receptor or provide ligands to the receptor, depending on the ratios of Wg, Fz2, and Dlp.National Institutes of Health American Cancer Society March of Dimes American Heart Associatio

NASA Developmental Biology Workshop: A summary

The Life Sciences Division of the National Aeronautics and Space Administration (NASA) as part of its continuing assessment of its research program, convened a workshop on Developmental Biology to determine whether there are important scientific studies in this area which warrant continued or expanded NASA support. The workshop consisted of six panels, each of which focused on a single major phylogenetic group. The objectives of each panel were to determine whether gravity plays a role in the ontogeny of their subject group, to determine whether the microgravity of spaceflight can be used to help understand fundamental problems in developmental biology, to develop the rationale and hypotheses for conducting NASA-relevant research in development biology both on the ground and in space, and to identify any unique equipment and facilities that would be required to support both ground-based and spaceflight experiments

The developmental cell biology of Trypanosoma brucei

Trypanosoma brucei provides an excellent system for studies of many aspects of cell biology, including cell structure and morphology, organelle positioning, cell division and protein trafficking. However, the trypanosome has a complex life cycle in which it must adapt either to the mammalian bloodstream or to different compartments within the tsetse fly. These differentiation events require stage-specific changes to basic cell biological processes and reflect responses to environmental stimuli and programmed differentiation events that must occur within a single cell. The organization of cell structure is fundamental to the trypanosome throughout its life cycle. Modulations of the overall cell morphology and positioning of the specialized mitochondrial genome, flagellum and associated basal body provide the classical descriptions of the different life cycle stages of the parasite. The dependency relationships that govern these morphological changes are now beginning to be understood and their molecular basis identified. The overall picture emerging is of a highly organized cell in which the rules established for cell division and morphogenesis in organisms such as yeast and mammalian cells do not necessarily apply. Therefore, understanding the developmental cell biology of the African trypanosome is providing insight into both fundamentally conserved and fundamentally different aspects of the organization of the eukaryotic cell

Coordination of cell division and differentiation in plants in comparison to animals

During animal and plant development all cells are originated from a single fertilized oocyte, the zygote. To generate an adult organism from the single-celled zygote many rounds of cell division are required to be completed. Cell division is manifested through a well-defined series of molecular and cellular events that is often referred as the cell cycle. Studies in various model organisms demonstrated that the eukaryotic cell cycle is regulated in a conserved manner with cyclin-dependent kinases (CDKs) in the centre. It is widely believed that cells must exit the cell cycle for cell differentiation. Accordingly, cell division and differentiation do not happen at the same time. The main questions in developmental biology are how these processes are coordinated during development, how do cells stop division before differentiation, and why and how cells maintain or re-initiate cell division activity? Recent studies indicate direct links between molecular cell cycle and cell differentiation machineries. The basic mechanisms regulating the balance between cell proliferation and differentiation are remarkably similar in plants and animals despite their fundamentally different developmental strategies. There is considerable dissimilarity, however, in the upstream signalling pathways affecting this balance in developmental and environmental contexts. In this chapter we focus our attention on the molecular regulatory mechanism controlling and coordinating cell division and differentiation both in animals and plants with emphasis on the entry and exit points of the cell cycle

Nina N. Moreira, MD, MS

Dr. Nina N. Moreira is an Associate in the Maternal Fetal Medicine Division of Obstetrics and Gynecology at the University of Iowa Hospitals and Clinics. She received a BS in Molecular, Cellular and Developmental Biology from Yale University. She completed her MD from the University of Texas Southwestern Medical Center at Dallas Southwestern Medical School. She completed an Obstetrics and Gynecology Residency at the University of Texas Southwestern/Parkland Health and Hospital System. She completed a Maternal-Fetal Medicine Fellowship in the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology at the University of Iowa Hospital and Clinics. She received a MS in Translational Biomedicine from the University of Iowa. Dr. Moreira sees patients in the Maternal Fetal Medicine and Prenatal Genetics Clinics

Nina N. Moreira, MD, MS

Dr. Nina N. Moreira is an Associate in the Maternal Fetal Medicine Division of Obstetrics and Gynecology at the University of Iowa Hospitals and Clinics. She received a BS in Molecular, Cellular and Developmental Biology from Yale University. She completed her MD from the University of Texas Southwestern Medical Center at Dallas Southwestern Medical School. She completed an Obstetrics and Gynecology Residency at the University of Texas Southwestern/Parkland Health and Hospital System. She completed a Maternal-Fetal Medicine Fellowship in the Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology at the University of Iowa Hospital and Clinics. She received a MS in Translational Biomedicine from the University of Iowa. Dr. Moreira sees patients in the Maternal Fetal Medicine and Prenatal Genetics Clinics

Developmental Context Determines Latency of MYC-Induced Tumorigenesis

One of the enigmas in tumor biology is that different types of cancers are prevalent in different age groups. One possible explanation is that the ability of a specific oncogene to cause tumorigenesis in a particular cell type depends on epigenetic parameters such as the developmental context. To address this hypothesis, we have used the tetracycline regulatory system to generate transgenic mice in which the expression of a c-MYC human transgene can be conditionally regulated in murine hepatocytes. MYC's ability to induce tumorigenesis was dependent upon developmental context. In embryonic and neonatal mice, MYC overexpression in the liver induced marked cell proliferation and immediate onset of neoplasia. In contrast, in adult mice MYC overexpression induced cell growth and DNA replication without mitotic cell division, and mice succumbed to neoplasia only after a prolonged latency. In adult hepatocytes, MYC activation failed to induce cell division, which was at least in part mediated through the activation of p53. Surprisingly, apoptosis is not a barrier to MYC inducing tumorigenesis. The ability of oncogenes to induce tumorigenesis may be generally restrained by developmentally specific mechanisms. Adult somatic cells have evolved mechanisms to prevent individual oncogenes from initiating cellular growth, DNA replication, and mitotic cellular division alone, thereby preventing any single genetic event from inducing tumorigenesis

Lessons from development: A role for asymmetric stem cell division in cancer

AbstractAsymmetric stem cell division has emerged as a major regulatory mechanism for physiologic control of stem cell numbers. Reinvigoration of the cancer stem cell theory suggests that tumorigenesis may be regulated by maintaining the balance between asymmetric and symmetric cell division. Therefore, mutations affecting this balance could result in aberrant expansion of stem cells. Although a number of molecules have been implicated in regulation of asymmetric stem cell division, here, we highlight known tumor suppressors with established roles in this process. While a subset of these tumor suppressors were originally defined in developmental contexts, recent investigations reveal they are also lost or mutated in human cancers. Mutations in tumor suppressors involved in asymmetric stem cell division provide mechanisms by which cancer stem cells can hyperproliferate and offer an intriguing new focus for understanding cancer biology. Our discussion of this emerging research area derives insight from a frontier area of basic science and links these discoveries to human tumorigenesis. This highlights an important new focus for understanding the mechanism underlying expansion of cancer stem cells in driving tumorigenesis

Streptomyces sporulation - Genes and regulators involved in bacterial cell differentiation

Streptomycetes are Gram-positive bacteria with a complex developmental life cycle. They form spores on specialized cells called aerial hyphae, and this sporulation involves alterations in growth, morphogenesis and cell cycle processes like cell division and chromosome segregation. Understanding the developmental mechanisms that streptomycetes have evolved for regulating for example cell division is of general interest in bacterial cell biology. It can also be valuable in the design of new drugs against bacterial pathogens. Very few sporulation genes have been found with an impact on cell cycle-related processes. Finding of such genes is important for a clarification of the molecular mechanisms that are underlying the developmental control of fundamental cellular processes in Streptomyces. The work of this thesis has led to the identification of genes previously unknown to be developmentally regulated in Streptomyces. By comparing the transcriptome of the wildtype S. coelicolor strain M145 to two developmental mutants, whiA and whiH, which specifically affect sporulation processes, it was possible to identify differentially expressed genes. Genes that so far have been characterized proved to have important roles during sporulation, affecting spore maturation, chromosome condensation and cell division. WhiH is a central regulator in the early sporulation process and required for the developmentally controlled form of cell division in S. coelicolor. In this thesis the role of WhiH as a transcription factor has been established and WhiH was found to bind to a specific site in its own promoter and function as an autoregulator. A whiHp-mCherry reporter fusion was used to monitor cell type-specific activity of the whiH promoter in aerial hyphae, and showed that it is active before delimitation of the sporogenic cell in which multiple developmentally controlled cell divisions will be triggered. A new Streptomyces model organism, S. venezuelae, was finally exploited to identify target genes for control by WhiH. This organism sporulates efficiently in liquid culture and is well suited for global transcriptomic approaches. In this study, microarray analysis of whiH-dependent gene expression was used to find putative targets for WhiH. Combined with chromatin-immunoprecipitation (ChIP-chip) and protein-DNA binding assays this identified a group of genes that are directly repressed by WhiH during a late stage of sporulation, and also some candidate genes that could be activated by WhiH at an earlier stage. Future analyses should shed light on the functions of these genes and their potential roles in developmental and cell cycle-related processes