Radiation embryology

Summary Prenatal development, characterized by intensive cell proliferation, cell differentiation and cell migration, shows a high radiosensitivity. Therefore, radiation exposure of embryos and fetuses is of great concern for radiological protection and human health. Irradiation during gestation can cause death, growth disorders, malformations, functional impairment and malignant diseases in childhood. These effects are strongly dependent on the developmental stage at exposure and on the radiation dose. The first trimester of pregnancy is regarded as the period with the highest risk for malformation and cancer induction. The developing nervous system shows a special susceptibility to ionizing radiation over a long period and is therefore of great significance for risk estimation. Knowledge about radiation effects on prenatal development has been derived from animal experimentation and from the exposure of human embryos. There is evidence that doses between 1 and 10 cGy may lead to developmental anomalies and that the radiation response can be modified by additional factors.     

Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces “aging-like” effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.     

(In)discrete charm of the polyembryony: Evolution of embryo cloning

Polyembryonic development, where multiple embryos are formed from a single zygote, evolved at least 15 times in six different phyla in animals. The mechanisms leading to polyembryony and the forces that shaped the evolution of the polyembryonic developmental program have remained poorly understood. Recent studies of the polyembryonic development in the endoparasitic wasp Copidosoma floridanum have revealed that the evolution of polyembryony is associated with the evolution of developmental novelties such as total cleavage, early specification of embryonic and extra-embryonic fates, and a specific cell proliferation phase. These changes cumulatively result in the formation of thousands of embryos from a single egg. Laser ablation studies and analysis of early cell fate specification have revealed that a single blastomere representing the progenitor of the primordial germ cell regulates the proliferation of the embryos. We propose that evolutionary changes in cell cleavage, cell interactions, and the cell-differentiation program, reminiscent of interactions between the germinal stem cell and stem cell niche in fly ovaries, underlies the evolution of polyembryony. Received 30 January 2007; received after revision 21 June 2007; accepted 11 July 2007     

Biological effectiveness of solar UV radiation in humans

Solar UVB radiation is prejudicial to the health of humans in a number of ways. Erythema and photodermatoses are acute reactions of the skin; keratitis and conjunctivitis are acute reactions of the eye. Various types of skin cancer, accelerated aging of the skin, and cataract formation in the crystalline lens are reactions that appear with great latency. UV radiation can also cause damage to the immune system and DNA. For the period 1981–1991, an increase in erythemal effective UVB radiation of +(7±4)% per decade was measured in a non-pulluted high mountain area (Jungfraujoch, 3576m a.s.l., Switzerland). This increase is related to a decrease in stratospheric ozone. The effects on human health are discussed. A 10% ozone reduction increases non-melanoma skin cancer by 26% and cataract by 6 to 8%.     

In vitro development of rat embryos obtained from diabetic mothers

Rat embryos of 9.5 or 10 days of gestation were removed from control or streptozotocin-diabetic mothers and cultured in normal rat serum (180 mg% glucose) or in diabetic serum (600 mg% glucose). The development of control embryos in normal serum was adequate. Embryos from normal mothers cultured in diabetic serum showed signs of developmental retardation. The development of embryos obtained from diabetic mothers was severely impaired, regardless of the gestational age or the culture medium. These results suggest that a diabetic maternal milieu produces irreversible effects in the embryo very early in gestation.     

Developmental genetics

Summary Of particular concern to the human geneticist are the effects of genetic abnormalities on development. To gain an understanding of these effects it is necessary to engage in a reciprocal process of using knowledge of normal developmental events to elucidate the mechanisms operative in abnormal situations and then of using what is learned about these abnormal situations to expand our understanding of the normal. True developmental genes have not been described in man, although it is likely that they exist, but many developmental abnormalities are ascribable to mutations in genes coding for enzymes and structural proteins. Some of these even produce multiple malformation syndromes with dysmorphic features. These situations provide a precedent for asserting that not only monogenic developmental abnormalities, but also abnormalities resulting from chromosome imbalance must ultimately be explicable in molecular terms. However, the major problem confronted by the investigator interested in the pathogenesis of any of the chromosome anomaly syndromes is to understand how the presence of an extra set of normal genes or the loss of one of two sets of genes has an adverse effect on development. Several molecular mechanisms for which limited precedents exist may be considered on theoretical grounds. Because of the difficulties in studying developmental disorders in man, a variety of experimental systems have been employed. Particularly useful has been the mouse, which provides models for both monogenic and aneuploidy produced abnormalities of development. An example of the former is the mutation oligosyndactylism which in the heterozygous state causes oligosyndactyly and in the homozygous state causes early embryonic mitotic arrest. All whole arm trisomies and monosomies of the mouse can be produced experimentally, and of special interest is mouse trisomy 16 which has been developed as an animal model of human trisomy 21 (Down syndrome). In the long run, the most direct approach to elucidating the genetic problems of human development will involve not only the study of man himself but also of the appropriate experimental models in other species.Acknowledgments. This review was written while the author was a Henry J. Kaiser Senior Fellow at the Center for Advanced Study in the Behavioral Sciences, Palo Alto, California. This work was supported by grants from the National Institutes of Health (GM-24309, HD-03132, HD-15583, HD-17001) and the American Cancer Society (CD-119) and by a contract from the National Institute of Child Health and Human Development (NOI-HD-2858).     

Developmental genetics

Of particular concern to the human geneticist are the effects of genetic abnormalities on development. To gain an understanding of these effects it is necessary to engage in a reciprocal process of using knowledge of normal developmental events to elucidate the mechanisms operative in abnormal situations and then of using what is learned about these abnormal situations to expand our understanding of the normal. True developmental genes have not been described in man, although it is likely that they exist, but many developmental abnormalities are ascribable to mutations in genes coding for enzymes and structural proteins. Some of these even produce multiple malformation syndromes with dysmorphic features. These situations provide a precedent for asserting that not only monogenic developmental abnormalities, but also abnormalities resulting from chromosome imbalance must ultimately be explicable in molecular terms. However, the major problem confronted by the investigator interested in the pathogenesis of any of the chromosome anomaly syndromes is to understand how the presence of an extra set of normal genes or the loss of one of two sets of genes has an adverse effect on development. Several molecular mechanisms for which limited precedents exist may be considered on theoretical grounds. Because of the difficulties in studying developmental disorders in man, a variety of experimental systems have been employed. Particularly useful has been the mouse, which provides models for both monogenic and aneuploidy produced abnormalities of development. An example of the former is the mutation oligosyndactylism which in the heterozygous state causes oligosyndactyly and in the homozygous state causes early embryonic mitotic arrest. All whole arm trisomies and monosomies of the mouse can be produced experimentally, and of special interest is mouse trisomy 16 which has been developed as an animal model of human trisomy 21 (Down syndrome). In the long run, the most direct approach to elucidating the genetic problems of human development will involve not only the study of man himself but also of the appropriate experimental models in other species.     

A note on the mechanism of action of UV-irradiation of amphibian embryos

The actions on amphibian embryos of UV-irradiation, exposure to Li+ or exposure to ouabain show interesting parallels with their effects on spontaneous release at the presynaptic terminals of the neuromuscular junction. It is suggested that these treatments serve to raise intracellular Ca2+ ([Ca2+]i) in these examples, and that UV-promoted abnormalities in embryogenesis are a consequence of changes in [Ca2+]i at critical stages in development.     

Cellular damage and recovery of the early developing mouse eye following low dose irradiation. I. X-rays on day 8 of gestation

Summary The eye region of mouse embryos, irradiated with 90 rad X-rays on day 8 of gestation, was examined 24 h later for cellular damage. Besides the overall developmental retardation, the radiation insult decreased the proliferation rate and altered the mitotic phase ratio. Due to the limited extension of necrotic zones, a reduced number of dead cells was found in the irradiated optic vesicles.Supported by the Swiss National Foundation for Scientific Research. The technical assistance of Mrs E. Frei is gratefully acknowledged.     

Hensen's node — The ’Organizer’ of the amniote embryo

Conclusion If the hundred years of study on theHensen's node — i.e. on gastrulation and early determination of the embryos of amniote vertebrates — teach anything, they teach in the first place how limited and fragmentary our knowledge is about one of the most central problems of the whole developmental biology. We know that the events in early amniote development — or early avian development, on which our data and ideas are nearly all based — in many ways resemble those in early Amphibian development, which is only slightly better understood, but we also know that direct extrapolations from anamniotes to amniotes cannot be made without proper reservations and without studying the amniote embryos themselves. And we have practically no idea of what is really going on in the cells of the blastoderm when they move, invaginate, induce or are induced, interact, become determined and begin their differentiation. We know that at the stages of gastrulation, the node, and indeed the whole blastoderm, is in a very labile state and can be regulated in many ways to produce a harmonious whole — or a monster — although we only understand very poorly the modes of this regulation. The progress made during the decades, and particularly in recent years, shows, however, that useful information is accumulating to produce a coherent picture, and there is no reason to be pessimistic.Dedicated to ProfessorEtienne Wolff on the occasion of his retirement.     

The inhibitory effect of D-glucosamine on thymidine kinase in chick embryo retinas and HeLa cells

D-Glucosamine markedly inhibits thymidine incorporation into the TCA-insoluble fraction and thymidine kinase activity in HeLa cells. Both the inhibitory effects are also observed in isolated retinas of chick embryos. In this case the inhibitory effects are age-dependent and the magnitude of the responses decreases with embryonic development. In addition the time of exposure to D-glucosamine which is necessary to reveal the inhibitory effect on thymidine kinase increases with the age of the embryos.     

The inhibitory effect of D-glucosamine on thymidine kinase in chick embryo retinas and HeLa cells

Summary D-Glucosamine markedly inhibits thymidine incorporation into the TCA-insoluble fraction and thymidine kinase activity in HeLa cells. Both the inhibitory effects are also observed in isolated retinas of chick embryos. In this case the inhibitory effects are age-dependent and the magnitude of the responses decreases with embryonic development. In addition the time of exposure to D-glucosamine which is necessary to reveal the inhibitory effect on thymidine kinase increases with the age of the embryos.     

In vitro neurogenesis: development and functional implications of iPSC technology

Neurogenesis is the developmental process regulating cell proliferation of neural stem cells, determining their differentiation into glial and neuronal cells, and orchestrating their organization into finely regulated functional networks. Can this complex process be recapitulated in vitro using induced pluripotent stem cell (iPSC) technology? Can neurodevelopmental and neurodegenerative diseases be modeled using iPSCs? What is the potential of iPSC technology in neurobiology? What are the recent advances in the field of neurological diseases? Since the applications of iPSCs in neurobiology are based on the capacity to regulate in vitro differentiation of human iPSCs into different neuronal subtypes and glial cells, and the possibility of obtaining iPSC-derived neurons and glial cells is based on and hindered by our poor understanding of human embryonic development, we reviewed current knowledge on in vitro neural differentiation from a developmental and cellular biology perspective. We highlight the importance to further advance our understanding on the mechanisms controlling in vivo neurogenesis in order to efficiently guide neurogenesis in vitro for cell modeling and therapeutical applications of iPSCs technology.     

Urea cycle and purinolysis in the embryos and pregnant females of the teleost fish Poecilia reticulata]

The presence of a functional ornithine-urea cycle is evidenced in the embryos of the viviparous Teleost Poecilia reticulata. The activity of the cycle decreases during developmental period but persists in adult tissues. Purinolytic (uricolytic) pathway is another source of urea in both embryos and adults. The implications of these findings are briefly discussed in relation to the problems of ureogenic and ureosmotic phenomena in Teleostean Fishes.     

Tracking migration during human T cell development

Specialized microenvironments within the thymus are comprised of unique cell types with distinct roles in directing the development of a diverse, functional, and self-tolerant T cell repertoire. As they differentiate, thymocytes transit through a number of developmental intermediates that are associated with unique localization and migration patterns. For example, during one particular developmental transition, immature thymocytes more than double in speed as they become mature T cells that are among the fastest cells in the body. This transition is associated with dramatic changes in the expression of chemokine receptors and their antagonists, cell adhesion molecules, and cytoskeletal components to direct the maturing thymocyte population from the cortex to medulla. Here we discuss the dynamic changes in behavior that occur throughout thymocyte development, and provide an overview of the cell-intrinsic and extrinsic mechanisms that regulate human thymocyte migration.     

A note on the mechanism of action of UV-irradiation of amphibian embryos

Summary The actions on amphibian embryos of UV-irradiation, exposure to Li⁺ or exposure to ouabain show interesting parallels with their effects on spontaneous release at the presynaptic terminals of the neuromuscular junction. It is suggested that these treatments serve to raise intracellular Ca²⁺ ([Ca²⁺ _i) in these examples, and that UV-promoted abnormalities in embryogenesis are a consequence of changes in [Ca²⁺]_i at critical stages in development.     

Resetting epigenetic signatures to induce somatic cell reprogramming

Somatic cell reprogramming consists of the induction of a complex sequence of events that results in the modification of the developmental state of the cell. It is now routinely possible to reprogram fully differentiated cells back to pluripotent cells, and to transdifferentiate cells of a given type in cells of a totally different lineage origin. However, whether there are key initiating factors that are distinct from those that control stem-cell renewal and that can initiate the reprogramming process remains unknown. In contrast, what is clear is that, by modifying the epigenetic status of a cell, its reprogramming can be initiated. Here, we review the current literature that shows how the plasticity of a cell can be modulated by modifying its epigenetic status, and we discuss how epigenetic barriers can be removed, to induce an efficient reprogramming process.     

The role of bystin in embryo implantation and in ribosomal biogenesis

Human bystin was identified as a cytoplasmic protein directly binding to trophinin, a cell adhesion molecule potentially involved in human embryo implantation. Although the trophinin gene is unique to mammals, the bystin gene (BYSL) is conserved across eukaryotes. Recent studies show that bystin plays a key role during the transition from silent trophectoderm to an active trophoblast upon trophinin-mediated cell adhesion. Bystin gene knockout and knockdown experiments demonstrate that bystin is essential for embryonic stem cell survival and trophectoderm development in the mouse. Furthermore, biochemical analysis of bystin in human cancer cells and mouse embryos indicates a function in ribosomal biogenesis, specifically in processing of 18S RNA in the 40S subunit. Strong evidence that BYSL is a target of c-MYC is consistent with a role for bystin in rapid protein synthesis, which is required for actively growing cells. Received 30 June 2007; received after revision 7 August 2007; accepted 29 August 2007