Journal: Seminars in cell & developmental biology
The circadian clock is an endogenous timer that anticipates and synchronizes biological processes to the environment. Traditional genetic approaches identified the underlying principles and genetic components, but new discoveries have been greatly impeded by the embedded redundancies that confer necessary robustness to the clock architecture. To overcome this, global (omic) techniques have provided a new depth of information about the Arabidopsis clock. Our understanding of the factors, regulation, and mechanistic connectivity between clock genes and with output processes has substantially broadened through genomic (cDNA libraries, yeast one-hybrid, protein binding microarrays, and ChIP-seq), transcriptomic (microarrays, RNA-seq), proteomic (mass spectrometry and chemical libraries), and metabolomic (mass spectrometry) approaches. This evolution in research will undoubtedly enhance our understanding of how the circadian clock optimizes growth and fitness.
Programmed cell death eliminates unneeded and dangerous cells in a timely and effective manner during development. In this review, we examine the role cell death plays during development in worms, flies and mammals. We discuss signaling pathways that regulate developmental cell death, and describe how they communicate with the core cell death pathways. In most organisms the majority of developmental cell death is seen in the nervous system. Therefore we focus on what is known about the regulation of developmental cell death in this tissue. Understanding how the cell death is regulated during development may provide insight into how this process can be manipulated in the treatment of disease.
The purpose of this review is to describe the endocrine and local testicular factors that contribute to the regulation of the blood-testis barrier (BTB), using information gained from in vivo and in vitro models of BTB formation during/after puberty, and from the maintenance of BTB function during adulthood. In vivo the BTB, in part comprised of tight junctions between adjacent somatic Sertoli cells, compartmentalizes meiotic spermatocytes and post-meiotic spermatids away from the vasculature, and therefore prevents autoantibody production by the immune system against these immunogenic germ cells. This adluminal compartment also features a unique biochemical milieu required for the completion of germ cell development. During the normal process of spermatogenesis, earlier germ cells continually cross into the adluminal compartment, but the regulatory mechanisms and changes in junctional proteins that allow this translocation step without causing a ‘leak’ remain poorly understood. Recent data describing the roles of FSH and androgen on the regulation of Sertoli cell tight junctions and tight junction proteins will be discussed, followed by an examination of the role of paracrine factors, including members of the TGFβ superfamily (TGFβ3, activin A) and retinoid signalling, as potential mediators of junction assembly and disassembly during the translocation process.
Macrophages are present in all tissues, either as resident cells or monocyte-derived cells that infiltrate into tissues. The tissue site largely determines the phenotype of tissue-resident cells, which help to maintain tissue homeostasis and act as sentinels of injury. Both tissue resident and recruited macrophages make a substantial contribution to wound healing following injury. In this review, we evaluate how macrophages in two fundamentally distinct tissues, i.e. the lung and the skin, differentially contribute to the process of wound healing. We highlight the commonalities of macrophage functions during repair and contrast them with distinct, tissue-specific functions that macrophages fulfill during the different stages of wound healing.
Exercise is the greatest physiological stress that our bodies experience. For example, during maximal endurance exercise in elite athlete’s cardiac output can increase up to 8-fold and the working muscles receive 21-times more blood each minute than at rest. Given the physiological stress associated with exercise and the adaptations that occur to handle this stress, it is not surprising that exercise training is known to prevent or effectively treat a multitude of degenerative conditions including cardiovascular disease, cancer, diabetes, depression, Alzheimer’s disease, Parkinson’s disease, and many others. Many of the health benefits of exercise are mediated by the mammalian/mechanistic target of rapamycin (mTOR), either in complex 1 or 2, not only within the working muscle, but also in distant tissues such as fat, liver, and brain. This review will discuss how exercise activates mTOR in diverse tissues and the ways that mTOR is important in the adaptive response that makes us bigger, stronger, and healthier as a result of exercise.
Loss-of-function mutations in the folliculin gene (FLCN) on chromosome 17p cause Birt-Hogg-Dube syndrome (BHD), which is associated with cystic lung disease. The risk of lung collapse (pneumothorax) in BHD patients is 50-fold higher than in the general population. The cystic lung disease in BHD is distinctive because the cysts tend to be basilar, subpleural and lentiform, differentiating BHD from most other cystic lung diseases. Recently, major advances in elucidating the primary functions of the folliculin protein have been made, including roles in mTOR and AMPK signaling via the interaction of FLCN with FNIP1/2, and cell-cell adhesion via the physical interaction of FLCN with plakophilin 4 (PKP4), an armadillo-repeat containing protein that interacts with E-cadherin and is a component of the adherens junctions. In addition, in just the last three years, the pulmonary impact of FLCN deficiency has been examined for the first time. In mouse models, evidence has emerged that AMPK signaling and cell-cell adhesion are involved in alveolar enlargement. In addition, the pathologic features of human BHD cysts have been recently comprehensively characterized. The “stretch hypothesis” proposes that cysts in BHD arise because of fundamental defects in cell-cell adhesion, leading to repeated respiration-induced physical stretch-induced stress and, over time, expansion of alveolar spaces particularly in regions of the lung with larger changes in alveolar volume and at weaker “anchor points” to the pleura. This hypothesis ties together many of the new data from cellular and mouse models of BHD and from the human pathologic studies. Critical questions remain. These include whether the consequences of stretch-induced cyst formation arise through a destructive/inflammatory program or a proliferative program (or both), whether cyst initiation involves a “second hit” genetic event inactivating the remaining wild-type copy of FLCN (as is known to occur in BHD-associated renal cell carcinomas), and whether cyst initiation involves exclusively the epithelial compartment versus an interaction between the epithelium and mesenchyme. Ultimately, understanding the mechanisms of cystic lung disease in BHD may help to elucidate the pathogenesis of primary spontaneous pneumothorax, with more than 20,000 cases reported annually in the United States alone .
While it is well-known that stress during development and adulthood can confer long-term neurobiological and behavioral consequences, investigators have only recently begun to assess epigenetic modifications associated with these consequences. In this review, we highlight clinical research and work with animal models that provide evidence of the impact of stressful experiences either during the perinatal period or adulthood on DNA methylation and behavior. Additionally, we explore the more controversial concept of transgenerational inheritance, including that associated with preconception stress experienced by the mother or father. Finally, we discuss challenges associated with the idea of transgenerational epigenetics and for the field of epigenetics in general.
Dietary restriction (DR, in the form of reduced calorie intake or alternate fasting with overall normal energy supply) elicits cell protective responses in nearly all tissues and organs including brain, and extends lifespan in a fashion that is conserved from the simplest model organisms to mammals and non-human primates. Importantly, studies on DR promise to reveal novel strategies to prolong healthspan and prevent age-related disorders in human beings. The present review focuses on the neuroprotective actions of DR as demonstrated by accumulating experimental and encouraging albeit still limited clinical and epidemiological data. Following an overview of the most relevant evidence for the benefit of DR on neurodegenerative disorders and brain ageing and damage in animals and human beings, the article will address the major mechanisms currently believed to participate in these effects, at a tissue (antiinflammation, enhanced adult neurogenesis and neuronal plasticity) and cellular (autophagy and mitochondrial biogenesis) level. Then it will “zoom-in” on the molecular circuitries (AMPK/mTOR, Sirtuins, CREB/Sirt-1) whereby neuronal cells perceive the reduced availability of nutrients and translate this information into protective adaptive responses. As a further development of this aspect, the emerging connection between cell metabolism and chromatin remodeling will be analysed, together with its relevance for our understanding of how food intake affects neuronal gene expression and brain health.
Genomically identical cells have long been assumed to comprise the human brain, with post-genomic mechanisms giving rise to its enormous diversity, complexity, and disease susceptibility. However, the identification of neural cells containing somatically generated mosaic aneuploidy-loss and/or gain of chromosomes from a euploid complement-and other genomic variations including LINE1 retrotransposons and regional patterns of DNA content variation (DCV), demonstrate that the brain is genomically heterogeneous. The precise phenotypes and functions produced by genomic mosaicism are not well understood, although the effects of constitutive aberrations, as observed in Down syndrome, implicate roles for defined mosaic genomes relevant to cellular survival, differentiation potential, stem cell biology, and brain organization. Here we discuss genomic mosaicism as a feature of the normal brain as well as a possible factor in the weak or complex genetic linkages observed for many of the most common forms of neurological and psychiatric diseases.
Polyploidy has been described in the liver for over 100 years. The frequency of polyploid hepatocytes varies by age and species, but up to 90% of mouse hepatocytes and approximately 50% of human hepatocytes are polyploid. In addition to alterations in the entire complement of chromosomes, variations in chromosome copy number have been recently described. Aneuploidy in the liver is pervasive, affecting 60% of hepatocytes in mice and 30-90% of hepatocytes in humans. Polyploidy and aneuploidy in the liver are closely linked, and the ploidy conveyor model describes this relationship. Diploid hepatocytes undergo failed cytokinesis to generate polyploid cells. Proliferating polyploid hepatocytes, which form multipolar spindles during cell division, generate reduced ploidy progeny (e.g., diploid hepatocytes from tetraploids or octaploids) and/or aneuploid daughters. New evidence suggests that random hepatic aneuploidy can promote adaptation to liver injury. For instance, in response to chronic liver damage, subsets of aneuploid hepatocytes that are differentially resistant to the injury remain healthy, regenerate the liver and restore function. Future work is required to elucidate the mechanisms regulating dynamic chromosome changes in the liver and to understand how these processes impact normal and abnormal liver function.