Genetic control of skeletal development

The skeleton is a single organ composed of >200 different elements spread throughout the body. These skeletal elements comprise two tissues: cartilage and bone. Both tissues contain specific cell type(s): chondrocytes in cartilage and osteoblasts and osteoclasts in bone. We are beginning to understand the genetic control of the differentiation and function of these cells through recent developments in mouse and human genetics, and also through the use of molecular biological and biochemical techniques. The most recent advances in terms of cell differentiation in the skeleton are presented in this review.     

Bone endocrine regulation of energy metabolism and male reproduction

Usually vertebrate physiology is studied within the confined limits of a given organ, if not cell type. This approach has progressively changed with the emergence of mouse genetics that has rejuvenated the concept of a whole body study of physiology. A vivid example of how mouse genetics has profoundly affected our understanding of physiology is skeleton physiology. A genetic approach to bone physiology revealed that bone via osteocalcin, an osteoblast-secreted molecule, is a true endocrine organ regulating energy metabolism and male reproduction. This ongoing body of work that takes bone out of its traditional roles is connecting it to a growing number of peripheral organs. These novel important hormonal connections between bone, energy metabolism and reproduction underscore the concept of functional dependence in physiology and the importance of genetic approaches to identify novel endocrine regulations.     

Osteopenic mice: animal models of the aging skeleton

While our understanding of the developmental biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics, we still know very little, in molecular and genetic terms, about skeletal physiology. Thus, among the many questions that are largely unexplained are the following: why is osteoporosis mainly a women's disease? How is bone mass maintained nearly constant between the end of puberty and the arrest of gonadal functions? Molecular genetics has emerged as a powerful tool to study previously unexplored aspects of the physiology of the skeleton. Among mammals, mice are the most promising animals for this experimental work. This has been previously demonstrated e.g. through the tremendous impact of the different osteopetrotic models on our molecular understanding of osteoclastic bone resorption. Until recently the only way of studying bone loss situations and osteoporosis in mice was by using ovariectomy with all its limitations. Today, however, we have access to more sophisticated osteoporotic mouse-models from four different origins: Transgenic mice (HSV-TK), knock-out mice (OPG), inbred-strains (SAMP6), and through physiological modulation (icv application). These new models have already taught us several important lessons. The first is, that bone remodeling is more than just an autocrine/paracrine process. Multiple experimental evidence has demonstrated that the latter regulation exists, but genetics prove that there is no functional cross-control between resorption and formation. The second lesson is, that remodeling is, at least in part, subject to central regulation. Thus, osteoporosis is partly a central or hypothalamic disease. However, the most dramatic change and the most important advantage we feel is, that today we have models to test a new hypothesis regarding the etiology of osteoporosis before it turns to dogma. Taken together, mouse-studies may lead to a shift in our physiological understanding of skeleton biology and to the emergence of novel paradigms. These, in turn, should help us to devise new treatments for degenerative diseases of the skeleton such as osteoporosis and its associated clinical problems.     

Transgenic and knock out mice in skeletal research. Towards a molecular understanding of the mammalian skeleton

Our understanding of the biology of the skeleton, like that of virtually every other subject in biology, has been transformed by recent advances in human and mouse genetics. Among mammals, mice are the most promising animals for this experimental work. Because extensive genetic information exists, many mouse mutations are known, and cells from early mouse developmental stages are accessible, scientists have developed transgenic mice - mice in which a gene is introduced or ablated in the germ line. Thus far, we have analyzed more than 100 different transgenic and knock out models with various skeletal phenotypes, covering the major aspects of both skeletal development and skeletal maintenance. Based on these results we here present a first perspective on transgenic and gene knock out animals in skeletal research, including insights in signaling pathways controlling endochondral bone formation, in the regulation of osteoblast function, osteoclastic bone resorption and in bone tumorigenesis, as well as the central control of bone formation. The use of transgenic mice to dissect and analyze regulatory mechanisms in bone cell physiology and the pathogenesis of human bone diseases is an extremely powerful experimental tool. The data presented here demonstrate that the successful convergence of novel genetic approaches with the established and fundamental knowledge of bone biology has made a beginning.     

Haloarchaeal proteases and proteolytic systems

Proteases play key roles in many biological processes and have numerous applications in biotechnology and industry. Recent advances in the genetics, genomics and biochemistry of the halophilic Archaea provide a tremendous opportunity for understanding proteases and their function in the context of an archaeal cell. This review summarizes our current knowledge of haloarchaeal proteases and provides a reference for future research.     

Defining functional gene‐circuit interfaces in the mouse nervous system

Complexity in the nervous system is established by developmental genetic programs, maintained by differential genetic profiles and sculpted by experiential and environmental influence over gene expression. Determining how specific genes define neuronal phenotypes, shape circuit connectivity and regulate circuit function is essential for understanding how the brain processes information, directs behavior and adapts to changing environments. Mouse genetics has contributed greatly to current percepts of gene‐circuit interfaces in behavior, but considerable work remains. Large‐scale initiatives to map gene expression and connectivity in the brain, together with advanced techniques in molecular genetics, now allow detailed exploration of the genetic basis of nervous system function at the level of specific circuit connections. In this review, we highlight several key advances for defining the function of specific genes within a neural network .     

The genetics of phytochrome signalling in Arabidopsis

The application of Arabidopsis genetics to research into the responses of plants to light has enabled rapid recent advances in this field. The plant photoreceptor phytochrome mediates well-defined responses that can be exploited to provide elegant and specific genetic screens. By this means, not only have mutants affecting the phytochromes themselves been isolated, but also mutants affecting the transduction of phytochrome signals. The genes involved in these processes have now begun to be characterized by using this genetic approach to isolate signal transduction components. Most of the components characterized so far are capable of being translocated to the cell nucleus, and they may help to define a new system of regulation of gene expression. This review summarises the ongoing contribution made by genetics to our understanding of light perception and signal transduction by the phytochrome system.     

The influence of genetics on future crop production strategies: from traits to genes, and genes to traits

This paper discusses how a genetical approach to plant physiology can contribute to research underpinning the production of new crop varieties. It highlights the interactions between genetics and plant breeding and how the current advances in genetics and the new science of genomics can contribute to our understanding of the genetical control of key agronomic traits ‐ the process of ‘translating’ traits to identified and mapped genes. Advances in genomics, such as the sequencing of whole genomes and expressed sequence tags, are producing information on genes and gene structures, but without knowing their function. A great deal more biology will be necessary to translate gene structure to function ‐ the process of translating genes to traits. Combining these ‘forward’ and ‘reverse’ genetic approaches will allow us to get comprehensive knowledge of the biology of agronomic traits at the physiological, biochemical and molecular levels, so that the ‘circuitry’ of our crop plants can be elucidated. This will enable plant breeders to manipulate crop phenotype using marker‐assisted breeding or genetic engineering approaches with a precision not previously possible.     

Probing bacterial pathogenesis with genetics, genomics, and chemical biology: past, present, and future approaches

Classical genetic approaches for studying bacterial pathogenesis have provided a solid foundation for our current understanding of microbial physiology and the interactions between pathogen and host. During the past decade however, advances in several arenas have expanded the ways in which the biology of pathogens can be studied. This review discussed the impact of these advances on bacterial genetics, including the application of genomics and chemical biology to the study of pathogenesis.     

The soybean cyst nematode, Heterodera glycines: a genetic model system for the study of plant-parasitic nematodes

Despite advances in understanding plant responses to nematode infection, little information exists regarding parasitic mechanisms. Recently, it has become possible to perform genetic analysis of soybean cyst nematode. Integration of classic and reverse genetics and genomic approaches for the parasite, with host genetics and genomics will expand our knowledge of nematode parasitism.     

Adaptive landscape genetics: pitfalls and benefits

Landscape genetics offers a promising framework for assessing the interactions between the environment and adaptive genetic variation in natural populations. A recent workshop held at the University of Neuchatel brought together leading experts in this field to address current insights and future research directions in adaptive landscape genetics. Considerable amounts of genetic and/or environmental data can now be collected, but the forthcoming challenge is to do more with such manna. This requires a markedly better understanding of the genetic variation that is adaptive and prompts for advances in information management together with the development of a balance between theory and data. Moreover, showing the links between landscapes and adaptive genetic variation will ultimately move the field beyond association studies.     

Contributions and promise of human behavioral genetics

Human behavioral genetics has contributed greatly to our understanding of human behavioral development. Twin, family, and adoption studies have shown that genetic effects are ubiquitous and that both genes and environments contribute to individual differences in behavior. The unique ability of behavioral genetic methods to separate genetic from environmental effects has also led to important discoveries about how the environment works in development and to the elucidation of the complex ways environments and genes interact across the life span. Although quantitative methods have been the mainstay of the field of human behavioral genetics since Galton's time, the Human Genome Project and advances in molecular genetics are providing new tools and promise as we enter the 21st century. Thus the future of human behavioral genetics lies in the cross-disciplinary exchanges and collaborations that will increasingly occur in the years to come among quantitative and molecular scientists who work with both animal and human systems. This research may someday culminate in an understanding of the biological basis of behavior that spans from how the brain develops and functions to a grasp of how genes influence thought at the molecular level.     

Present problems of somatic cell genetics]

A review of recent advances in genetics of somatic cells is given in the article. It contains three sections: 1) hybridization of somatic cells and its application to the mapping of genes and to the study of gene action; 2) relation of somatic cell genetics to genetic engineerings; 3) progress and perspectives of higher plant somatic cell genetics.     

The co-evolutionary genetics of ecological communities

Co-evolution has produced many intriguing adaptations and made significant contributions to biodiversity through the co-adaptive radiations of interacting groups, such as pollinating insects and flowering plants or hosts and endosymbionts. New methods from molecular genetics and comparative genomics, in conjunction with advances in evolutionary genetic theory, are for the first time providing tools for detecting, investigating and understanding the genetic bases of the co-adaptive process and co-speciation. Advances in the emerging field of community genetics, which integrates genetics and community ecology, could revolutionize how co-evolution is studied, how genes are functionally annotated and how conservation geneticists implement preservation strategies.     

Understanding of genetic information in higher secondary students in northeast India and the implications for genetics education

Since the work of Watson and Crick in the mid-1950s, the science of genetics has become increasingly molecular. The development of recombinant DNA technologies by the agricultural and pharmaceutical industries led to the introduction of genetically modified organisms (GMOs). By the end of the twentieth century, reports of animal cloning and recent completion of the Human Genome Project (HGP), as well techniques developed for DNA fingerprinting, gene therapy and others, raised important ethical and social issues about the applications of such technologies. For citizens to understand these issues, appropriate genetics education is needed in schools. A good foundation in genetics also requires knowledge and understanding of topics such as structure and function of cells, cell division, and reproduction. Studies at the international level report poor understanding by students of genetics and genetic technologies, with widespread misconceptions at various levels. Similar studies were nearly absent in India. In this study, I examine Indian higher secondary students' understanding of genetic information related to cells and transmission of genetic information during reproduction. Although preliminary in nature, the results provide cause for concern over the status of genetics education in India. The nature of students' conceptual understandings and possible reasons for the observed lack of understanding are discussed.     

The actin membrane skeleton in Drosophila development

Movements, manifest as changes in cell arrangements and shape, are an integral part of metazoan development. The molecular basis of such movements is only now being understood. Drosophila offers an excellent opportunity to apply powerful classical and modern molecular genetic methods to the analysis of movements during development. Moreover, the genes that contribute to pattern formation in fly development are under intense investigation. The future promises to illuminate how such genes regulate the structure and function of the membrane skeleton. This review is a progress report on our current understanding of the membrane skeleton in Drosophila.     

Toxicology and genetic toxicology in the new era of "toxicogenomics": impact of "-omics" technologies.

The unprecedented advances in molecular biology during the last two decades have resulted in a dramatic increase in knowledge about gene structure and function, an immense database of genetic sequence information, and an impressive set of efficient new technologies for monitoring genetic sequences, genetic variation, and global functional gene expression. These advances have led to a new sub-discipline of toxicology: "toxicogenomics". We define toxicogenomics as "the study of the relationship between the structure and activity of the genome (the cellular complement of genes) and the adverse biological effects of exogenous agents". This broad definition encompasses most of the variations in the current usage of this term, and in its broadest sense includes studies of the cellular products controlled by the genome (messenger RNAs, proteins, metabolites, etc.). The new "global" methods of measuring families of cellular molecules, such as RNA, proteins, and intermediary metabolites have been termed "-omic" technologies, based on their ability to characterize all, or most, members of a family of molecules in a single analysis. With these new tools, we can now obtain complete assessments of the functional activity of biochemical pathways, and of the structural genetic (sequence) differences among individuals and species, that were previously unattainable. These powerful new methods of high-throughput and multi-endpoint analysis include gene expression arrays that will soon permit the simultaneous measurement of the expression of all human genes on a single "chip". Likewise, there are powerful new methods for protein analysis (proteomics: the study of the complement of proteins in the cell) and for analysis of cellular small molecules (metabonomics: the study of the cellular metabolites formed and degraded under genetic control). This will likely be extended in the near future to other important classes of biomolecules such as lipids, carbohydrates, etc. These assays provide a general capability for global assessment of many classes of cellular molecules, providing new approaches to assessing functional cellular alterations. These new methods have already facilitated significant advances in our understanding of the molecular responses to cell and tissue damage, and of perturbations in functional cellular systems.As a result of this rapidly changing scientific environment, regulatory and industrial toxicology practice is poised to undergo dramatic change during the next decade. These advances present exciting opportunities for improved methods of identifying and evaluating potential human and environmental toxicants, and of monitoring the effects of exposures to these toxicants. These advances also present distinct challenges. For example, the significance of specific changes and the performance characteristics of new methods must be fully understood to avoid misinterpretation of data that could lead to inappropriate conclusions about the toxicity of a chemical or a mechanism of action. We discuss the likely impact of these advances on the fields of general and genetic toxicology, and risk assessment. We anticipate that these new technologies will (1) lead to new families of biomarkers that permit characterization and efficient monitoring of cellular perturbations, (2) provide an increased understanding of the influence of genetic variation on toxicological outcomes, and (3) allow definition of environmental causes of genetic alterations and their relationship to human disease. The broad application of these new approaches will likely erase the current distinctions among the fields of toxicology, pathology, genetic toxicology, and molecular genetics. Instead, a new integrated approach will likely emerge that involves a comprehensive understanding of genetic control of cellular functions, and of cellular responses to alterations in normal molecular structure and function.     

Hereditary disorders of the red cell membrane skeleton

The hereditary hemolytic anemias include a heterogeneous class of disorders caused by defects in the proteins that constitute the membrane skeleton of the red blood cell. The combination of classical and molecular genetics together with clinical findings is rapidly improving our understanding of the basis of these defects.     

Dystrophin and disease.

Recent advances concerning the genetic and biochemical basis of Duchenne and Becker muscular dystrophies have resulted in a good understanding of the etiology of these common dystrophies. An important secondary consequence of the genetic and biochemical research has been the generation of gene-based and protein-based diagnostic tools which enable a 'molecular diagnosis' for patients and their families. This review summarizes our current understanding of the genetics, biochemistry, and pathophysiology of Duchenne dystrophy, and gives an overview of the molecular diagnostic tools and their applications. Recent correlations of clinical, genetic and biochemical data have indicated that dystrophinopathies can present with a wide range of neuromuscular symptoms, and that neither male sex nor proximal weakness are diagnostic prerequisites for consideration of an underlying dystrophin abnormality.     

Architecture and development of the Neurospora crassa hypha -- a model cell for polarized growth

Neurospora crassa has been at the forefront of biological research from the early days of biochemical genetics to current progress being made in understanding gene and genetic network function. Here, we discuss recent developments in analysis of the fundamental form of fungal growth, development and proliferation -- the hypha. Understanding the establishment and maintenance of polarity, hyphal elongation, septation, branching and differentiation are at the core of current research. The advances in the identification and functional dissection of regulatory as well as structural components of the hypha provide an expanding basis for elucidation of fundamental attributes of the fungal cell. The availability and continuous development of various molecular and microscopic tools, as utilized by an active and co-supportive research community, promises to yield additional important new discoveries on the biology of fungi.