From milk to malignancy: the role of mammary stem cells in development, pregnancy and breast cancer

Adult stem cells of the mammary gland (MaSCs) are a highly dynamic population of cells that are responsible for the generation of the gland during puberty and its expansion during pregnancy. In recent years significant advances have been made in understanding how these cells are regulated during these developmentally important processes both in humans and in mice. Understanding how MaSCs are regulated is becoming a particularly important area of research, given that they may be particularly susceptible targets for transformation in breast cancer. Here, we summarize the identification of MaSCs, how they are regulated and the evidence for their serving as the origins of breast cancer. In particular, we focus on how changes in MaSC populations may explain both the increased risk of developing aggressive ER/PR(-) breast cancer shortly after pregnancy and the long-term decreased risk of developing ER/PR(+) tumors.     

Signaling in Cell Differentiation and Morphogenesis

All the information to make a complete, fully functional living organism is encoded within the genome of the fertilized oocyte. How is this genetic code translated into the vast array of cellular behaviors that unfold during the course of embryonic development, as the zygote slowly morphs into a new organism? Studies over the last 30 years or so have shown that many of these cellular processes are driven by secreted or membrane-bound signaling molecules. Elucidating how the genetic code is translated into instructions or signals during embryogenesis, how signals are generated at the correct time and place and at the appropriate level, and finally, how these instructions are interpreted and put into action, are some of the central questions of developmental biology. Our understanding of the causes of congenital malformations and disease has improved substantially with the rapid advances in our knowledge of signaling pathways and their regulation during development. In this article, I review some of the signaling pathways that play essential roles during embryonic development. These examples show some of the mechanisms used by cells to receive and interpret developmental signals. I also discuss how signaling pathways downstream from these signals are regulated and how they induce specific cellular responses that ultimately affect cell fate and morphogenesis.     

Genetic, environmental and maternal influences on embryonic cardiac rhythms

The relative roles of an animal's genetic constituents and environmental factors in influencing physiological variables such has heart rate have not been extensively investigated. This paper considers how heart rate patterns in the developing animal can be regulated, and how a combination of 'nature' and 'nurture' may interact to produce discrete patterns of heart rate change during development. The concept of the 'developmental trajectory' is evoked to generate a conceptual framework for how physiological development can be perturbed by environmental factors. Data are provided from three species showing how 'clutch-effects' (the fact that siblings perform physiologically much more similarly than non-siblings) can greatly influence the variance observed when collecting data on heart rate during development. Finally, so-called 'maternal effects', which are the influences on embryos of environmental experiences of the parents, are discussed as potentially confounding effects in the study of the genetic basis for physiological patterns of change during development.     

Maintaining youth in Drosophila neural progenitors

An important question is how dividing stem cells maintain competence to generate multiple cell types, whereas most other cells become progressively restricted during development. The molecular basis for progenitor competence--or how competence is progressively restricted--has remained mysterious. Recent work has shown that Drosophila neuroblasts and mammalian neural progenitors are more similar than previously appreciated, and provide an excellent model system for using Drosophila genetics to unravel the molecular nature of progenitor competence and how it becomes progressively restricted during development.     

Maintaining Youth in Drosophila Neural Progenitors

An important question is how dividing stem cells maintain competence to generate multiple cell types, whereas most other cells become progressively restricted during development. The molecular basis for progenitor competence – or how competence is progressively restricted – has remained mysterious. Recent work has shown that Drosophila neuroblasts and mammalian neural progenitors are more similar than previously appreciated, and provide an excellent model system for using Drosophila genetics to unravel the molecular nature of progenitor competence and how it becomes progressively restricted during development     

Roles of Rho GTPases in leucocyte and leukaemia cell transendothelial migration

Leucocytes migrate into and out of blood vessels at multiple points during their development and maturation, and during immune surveillance. In response to tissue damage and infection, they are rapidly recruited through the endothelium lining blood vessels into the tissues. Leukaemia cells also move in and out of the bloodstream during leukaemia progression. Rho GTPases are intracellular signalling proteins that regulate cytoskeletal dynamics and are key coordinators of cell migration. Here, we describe how different members of the Rho GTPase family act in leucocytes and leukaemia cells to regulate steps of transendothelial migration. We discuss how inhibitors of Rho signalling could be used to reduce leucocyte or leukaemia cell entry into tissues.     

Cell Optical Density and Molecular Composition Revealed by Simultaneous Multimodal Label-Free Imaging

We show how Raman imaging can be combined with independent but simultaneous phase measurements of unlabeled cells, with the resulting data providing information on how the light is retarded and/or scattered by molecules in the cell. We then show, for the first time to our knowledge, how the chemistry of the cell highlighted in the Raman information is related to the cell quantitative phase information revealed in digital holographic microscopy by quantifying how the two sets of spatial information are correlated. The results show that such a multimodal implementation is highly useful for the convenience of having video rate imaging of the cell during the entire Raman measurement time, allowing us to observe how the cell changes during Raman acquisition. More importantly, it also shows that the two sets of label-free data, which result from different scattering mechanisms, are complementary and can be used to interpret the composition and dynamics of the cell, where each mode supplies label-free information not available from the other mode.     

Cell Optical Density and Molecular Composition Revealed by Simultaneous Multimodal Label-Free Imaging

We show how Raman imaging can be combined with independent but simultaneous phase measurements of unlabeled cells, with the resulting data providing information on how the light is retarded and/or scattered by molecules in the cell. We then show, for the first time to our knowledge, how the chemistry of the cell highlighted in the Raman information is related to the cell quantitative phase information revealed in digital holographic microscopy by quantifying how the two sets of spatial information are correlated. The results show that such a multimodal implementation is highly useful for the convenience of having video rate imaging of the cell during the entire Raman measurement time, allowing us to observe how the cell changes during Raman acquisition. More importantly, it also shows that the two sets of label-free data, which result from different scattering mechanisms, are complementary and can be used to interpret the composition and dynamics of the cell, where each mode supplies label-free information not available from the other mode.     

DNA-binding antibodies and parasitic diseases

DNA-binding antibodies are produced during the course of many parasitic infections, including malaria, leprosy and schistosomiasis. These antibodies are also present in certain autoimmune diseases, such as systemic lupus erythematosus, and much information is available about their properties and contribution to related disease processes Here, Anne Wozencraft and Norman Staines consider how DNA-binding antibodies might arise during parasitic infection and discuss how an increased knowledge of their properties and functions could lead to a greater understanding of mechanisms of immuno-pathology in these diseases.     

Derivation and maintenance of human embryonic stem cells from poor-quality in vitro fertilization embryos

Human embryonic stem (hES) cells are self-renewing, pluripotent cells that are valuable research tools and hold promise for use in regenerative medicine. Most hES cell lines are derived from cryopreserved human embryos that were created during in vitro fertilization (IVF) and are in excess of clinical need. Embryos that are discarded during the IVF procedure because of poor morphology and a low likelihood for generating viable pregnancies or surviving the cryopreservation process are also a viable source of hES cells. In this protocol, we describe how to derive novel hES cells from discarded poor-quality embryos and how to maintain the hES cell lines.     

Experiments,measurements, and mathematical modeling to decipher time signals in development

Good progress has been made in identifying key signaling molecules and explaining how they are used to generate spatial patterns during embryonic development. In contrast, little is known about the control of timing or how cells use time signals in the developing embryo. In this review, I describe how direct measurements from the embryo combined with mathematical modeling could bring new insights. To illustrate this point, I discuss three examples: the Dpp gradient during growth of the Drosophila wing imaginal disc; the Polycomb‐based epigenetic silencing during vernalization in plants; and the Notch‐dependent somite segmentation clock. Birth Defects Research (Part C) 96:121–131, 2012. © 2012 Wiley Periodicals, Inc.     

Protozoan encounters with Toll-like receptor signalling pathways: implications for host parasitism

Toll-like receptors (TLRs) have emerged as a major receptor family involved in non-self recognition. They have a vital role in triggering innate immunity and orchestrate the acquired immune response during bacterial and viral infection. However, the role of TLRs during infection with protozoan pathogens is less clear. Nevertheless, our understanding of how these parasitic microorganisms engage the host TLR signalling system has now entered a phase of rapid expansion. This Review describes recent insights into how parasitic protozoans are sensed by TLR molecules, and how the TLR system itself can be targeted by these microbial pathogens for their own survival.     

Autophagy and innate immunity: Triggering,targeting and tuning

Autophagy is a conserved catabolic stress response pathway that is increasingly recognized as an important component of both innate and acquired immunity to pathogens. The activation of autophagy during infection not only provides cell-autonomous protection through lysosomal degradation of invading pathogens (xenophagy), but also regulates signaling by other innate immune pathways. This review will focus on recent advances in our understanding of three major areas of the interrelationship between autophagy and innate immunity, including how autophagy is triggered during infection, how invading pathogens are targeted to autophagosomes, and how the autophagy pathway participates in “tuning” the innate immune response.     

Chromosome segregation in Eubacteria

It is now clear that bacterial chromosomes rapidly separate in a manner independent of cell elongation, suggesting the existence of a mitotic apparatus in bacteria. Recent studies of bacterial cells reveal filamentous structures similar to the eukaryotic cytoskeleton, proteins that mediate polar chromosome anchoring during Bacillus subtilis sporulation, and SMC interacting proteins that are involved in chromosome condensation. A picture is thereby developing of how bacterial chromosomes are organized within the cell, how they are separated following duplication, and how these processes are coordinated with the cell cycle.     

Physiological and circuit mechanisms of postural control

The postural system maintains a specific body orientation and equilibrium during standing and during locomotion in the presence of many destabilizing factors (external and internal). Numerous studies in humans have revealed essential features of the functional organization of this system. Recent studies on different animal models have significantly supplemented human studies. They have greatly expanded our knowledge of how the control system operates, how the postural functions are distributed within different parts of CNS, and how these parts interact with each other to produce postural corrections and adjustments. This review outlines recent advances in the studies of postural control in quadrupeds, with special attention given the neuronal postural mechanisms.     

EVOLUTION AND MORPHOGENETIC RULES: THE SHAPE OF THE VERTEBRATE LIMB IN ONTOGENY AND PHYLOGENY

The notion of a “developmental constraint” has become a catchphrase for a collection of poorly defined notions about how ontogeny affects phylogeny. In this paper, we shall attempt to define this idea more precisely by examining the vertebrate limb from three viewpoints. First, theoretical models of morphogenesis suggest several generalizations about how limb geometry is laid down during development. Comparative studies and experimental manipulations of developing limbs independently confirm these generalizations, which amount to a set of “construction rules” for determining how the major features of limb architecture are established in ontogeny. Armed with these rules, we can inquire how limb morphology can be varied during evolution and suggest a more precise operational definition of “developmental constraints” on morphological evolution.     

Tissue repair and the dynamics of the extracellular matrix

Repair of tissue after injury depends on the synthesis of a fibrous extracellular matrix to replace lost or damaged tissue. Newly deposited extracellular matrix is then re-modeled over time to emulate normal tissue. The extracellular matrix directs repair by regulating the behavior of the wide variety of cell types that are mobilized to the damaged area in order to rebuild the tissue. Acute inflammation, re-epithelialization, and contraction all depend on cell-extracellular matrix interactions and contribute to minimize infection and promote rapid wound closure. Matricellular proteins are up-regulated during wound healing where they modulate interactions between cells and the extracellular matrix to exert control over events that are essential for efficient tissue repair. Here, we discuss how the extracellular matrix changes during the stages of tissue repair, how matricellular proteins affect cell-extracellular matrix interactions, and how these proteins might be exploited for use therapeutically.     

Mature neurons: equipped for survival

Neurons completely transform how they regulate cell death over the course of their lifetimes. Developing neurons freely activate cell death pathways to fine-tune the number of neurons that are needed during the precise formation of neural networks. However, the regulatory balance between life and death shifts as neurons mature beyond early development. Mature neurons promote survival at all costs by employing multiple, often redundant, strategies to prevent cell death by apoptosis. This dramatic shift from permitting cell death to ensuring cellular survival is critical, as these post-mitotic cells must provide neuronal circuitry for an organism''s entire lifetime. Importantly, as many neurodegenerative diseases afflict adult neuronal populations, the survival mechanisms in mature neurons are likely to be either reversed or circumvented during neurodegeneration. Examining the adaptations for inhibiting apoptosis during neuronal maturation is key to comprehending not just how neurons survive long term, but may also provide insight for understanding how neuronal toxicity in various neurodegenerative diseases may ultimately lead to cell death.     

Bone Morphogenetic Protein functions as a context-dependent angiogenic cue in vertebrates

Bone Morphogenetic Protein (BMP) signaling has been implicated in diverse biological processes. Although how BMP signaling regulates behaviors of endothelial cells during angiogenesis are not fully understood, increasing evidence indicate functions of BMP signaling components are essential in developmental and pathological angiogenesis. Here we review recent advances in delineating the functions of BMP signaling during angiogenesis. In addition, we discuss downstream pathways that transduce BMP signaling in endothelial cells, and factors that modulate BMP signaling response in endothelial cells. Finally, we provide recent insight on how BMP signaling functions as a context dependent angiogenic cue.