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PubMedDate not supplied

Mutational analyses of lymphocyte differentiation.

The site-specific recombination mechanism responsible for the assembly of antigen receptor variable region genes is only employed in lymphocyte development. Gene-targeted and other types of mutational analyses have implicated at least seven distinct gene products, some lymphoid-specific and others more generally expressed, as involved in aspects of this process. Mutation of the lymphocyte-specific activities required for VDJ recombination or mutation of the target gene segments of this process have created B and/or T cell-deficient mouse models that have provided new insights into the regulation of the VDJ recombination reaction and into how the successful achievement of this reaction at various loci helps lead lymphocytes through their early developmental program A second type of B lymphocyte-specific recombination process is involved in heavy-chain class switching; gene-targeted mutation approaches also have provided new insights into the cis-acting elements that target of this reaction to particular CH genes.

Animals↗

PubMed1992

Developmental hierarchy during early human B-cell ontogeny after autologous bone marrow transplantation using autografts depleted of CD19+ B-cell precursors by an anti-CD19 pan-B-cell immunotoxin containing pokeweed antiviral protein.

Sequential immunophenotypes of bone marrow (BM) and peripheral blood (PBL) lymphoid cells from 15 B-lineage acute lymphoblastic leukemia (ALL) patients who underwent autologous bone marrow transplantation (BMT) during complete remission were determined by dual-color immunofluorescence and multiparameter flow cytometry. Autografts were depleted of CD19+ B-cell precursors by an immunochemopurging protocol that combines B43-PAP, a potent anti-CD19 immunotoxin, and the cyclophosphamide congener 4-hydroperoxycyclophosphamide (4-HC). A marked interpatient variation was observed in the appearance and expansion of B-cell precursors repopulating the posttransplant marrow. The expression of CD10 and CD19 antigens during early B-cell ontogeny post-BMT preceded the expression of CD20, CD21, CD22, CD40, and sIgM. The surface antigen profiles of the emerging B-cell precursors were similar to those of fetal liver or fetal bone marrow B-cell precursors. Our comparisons of BM and PBL samples from patients in the early post-BMT period demonstrated that (1) PBL initially contains fewer B-lineage cells than does BM, and (2) circulating B-lineage lymphoid cells have a more mature immunophenotype than do BM B-lineage lymphoid cells. Comparison of the surface antigen profiles of day 30 versus day 100 or year 1 BM or PBL lymphoid cells showed an increase in the percentages of CD10+CD22- undifferentiated lymphocyte precursors, as well as CD19+sIgM- B-cell precursors (pre-pre-B), consistent with a time-dependent expansion of these B-cell precursor populations post-BMT. Importantly, the percentages of CD10+CD22+ and CD19+sIgM+ B-cell precursor (pre-B) populations also increased between 30 days and 1 year post-BMT, confirming the ability of emerging immature B-cell precursors to differentiate along the B-precursor pathway. The acquisition and expression of B-lineage differentiation antigens at different stages of the post-BMT B-cell ontogeny support the notion that the expression of these antigens is developmentally programmed. Similar to patients in previous autologous BMT studies, recipients of B-cell precursor-depleted autografts had normal or nearly normal serum immunoglobulin levels, suggesting that the maturing B-cell/plasma cell populations can produce and secrete immunoglobulins. The development of a functional CD19+ B-lineage lymphoid compartment in recipients of autografts which were depleted of CD19+ B-cell precursors corroborates the previously postulated existence of CD19- B-lineage lymphoid progenitor cells.

Antigens, CD↗

PubMed1992

Murine models of normal and neoplastic human haematopoiesis.

The ability to transplant human haematopoietic cells into immune deficient mice provides a unique opportunity for studying the organization and regulation of the human stem cell developmental program. One challenge for the future will be to reconstitute mice with functional cells of all lineages. The creation of animal models of many haematopoietic diseases should revolutionize the development and testing of novel therapeutic strategies. Significant progress has been made in establishing models of human neoplastic diseases such as leukaemia and lymphoma. Although the number of patients examined is still small, it appears that there may be a correlation between growth in immune deficient mice and clinical outcome. Future studies should examine the range of diseases that grow in mice and whether in vivo assays have prognostic value clinically. These leukaemia models, in conjunction with high efficiency gene transfer techniques, offer a powerful approach to examine the biological consequences of expressing oncogenes or other key regulatory genes on human leukaemic transformation and progression.

Animals↗

PubMed2003

[Onecut transcription factors: role in the development of the pancreas and the liver].

The development of the organism involves the formation of tissues that differ by the morphology and functions of the cells they contain. This results from the synthesis, coordinated in time and space, of a tissue-specific set of proteins. Transcription factors, which control gene expression, play a crucial role in this process. We have discovered a family of tissue-restricted transcription factors, called Onecut, whose prototype is HNF-6 (OC-1) and the two other mammalian members are OC-2 and OC-3. During embryogenesis, HNF-6 controls in the endoderm the transcription of genes which code for other transcription factors. In this way, HNF-6 regulates several developmental programs. To identify these programs, we have inactivated the Hnf6 gene in the mouse. This has shown that HNF-6 is a key factor in pancreas development and its endocrine differentiation, as well as in formation of the biliary tract. The Hnf6-/- mice develop diabetes mellitus and cholestasis. The patterns of expression of OC-2 and OC-3 superimpose partially, and coincide in part with that of HNF-6. This suggests functional interactions between the OC factors during tissue differentiation. We are tackling this question by studying the phenotype of mice in which one or several Onecut genes have been inactivated.

Animals↗

PubMedDate not supplied

Use of Xenopus laevis frog egg extract in diagnosing human male unexplained infertility.

Approximately one in six married couples find themselves involuntarily infertile. This ratio translates to between two and four million U.S. couples. Although numerous tests are available for diagnosing infertility problems, 5-10 percent of all couples who seek medical treatment are diagnosed with unexplained infertility. Several tests are presently available for diagnosing male infertility; however, none of the present procedures test for activation of the sperm nucleus following entry into the fertilized egg, a series of events critical for the entry of the zygote into the developmental program. We have developed an in vitro human sperm activation assay, using Xenopus laevis frog egg extract. When normal human sperm is permeabilized and then mixed with frog egg extract, the sperm nuclei decondense, synthesize DNA, and recondense during a three-hour time course. We have tested this assay's utility in diagnosing previously unexplained infertility. We found that 20 percent of the male infertility patients produced sperm that responded abnormally in the assay (95 percent confidence interval, 4-48 percent; n = 15), while sperm samples from 15 fertile males showed no abnormal responses (p = 0.0112). These preliminary results indicate that the human sperm activation assay may be a useful tool for diagnosing some cases of human infertility.

Animals↗

PubMed1978

Intelligence levels of Down's syndrome children.

Intelligence levels of a sample of 180 Down's syndrome children were reported, and the results indicated that their abilities are not as limited as previously thought. The introduction of special developmental programs from birth onwards appears to have promoted an increase in intellectual development. Lack of extended educational opportunity may account for the apparent decrease in intellectual function in Down's syndrome adolescents. It is suggested that school placement be based on demonstrated present ability rather than assumed long-term potential inferred from autosomal and physical characteristics.

Adolescent↗

PubMedDate not supplied

[Protocortex versus protomap: a perspective from the olfactory bulb].

INTRODUCTION AND AIM: The olfactory sensory system is a unique model for the research of guidance and connectivity of growing axons. During development, the olfactory epithelium, the olfactory bulb and the olfactory cortex differentiate several cell types and extend projection axons. Because there is a close relationship between these three structures, we ask the question as to whether establishment of the olfactory bulb central projections can proceed independently of the arrival of the olfactory sensory afferents. This raises another more general question: is establishment of afferent connections necessary to awake a developmental program in target cells?. DEVELOPMENT: The initial establishment of the olfactory bulb central projections occurs independently of the arrival of the olfactory axons from the olfactory epithelium, which reinforces the idea that cortical regions are already patterned before migration of newborn neurons, at least for the olfactory bulb and maybe for the entire brain. This implies a strict intrinsic molecular control of the distinct olfactory structures, independent one of each other. CONCLUSIONS: How then, do axonal projections find their correct way within the brain? Contact-mediated mechanisms and chemotropic molecules cooperate to fix their position in the telencephalon, prevent bulbar axons from invading structures other than the olfactory cortex and, at the same time, stimulate axonal branching in an orchestra of both, attractive/promoting and repulsive/inhibiting signals. At later stages, the mature appearance of the olfactory bulb will be completed and refined.

Animals↗

PubMed1992

Characterization of human brain cDNA encoding the general isoform of beta-spectrin.

The complete primary structure of the general form of human beta-spectrin (beta G) has been deduced from cDNAs isolated from human brain. beta G-Spectrin is encoded by a gene located on human chromosome 2. beta G-Spectrin and erythrocyte beta-spectrin (beta R) share identical domain organization, with sequence identity of 60% and sequence similarity of 77%. beta-Spectrins have closely related N-terminal domains implicated in binding to actin, and 17 copies of a 106-residue repeat motif with consensus residues that are highly conserved between beta-spectrins as well as alpha-spectrins. C-terminal domains of beta G and the 270-kDa beta R-spectrins are candidate regions to associate with alpha-spectrin, and exhibit 75% similarity. beta G- and beta R-spectrins exhibit different patterns of expression in tissues and follow different developmental programs in those tissues where they are co-expressed. beta G-Spectrin is present in all tissues examined except for erythrocytes, while beta R-spectrin could be detected only in erythrocytes, brain, and heart. beta G- and beta R-Spectrins are both expressed in brain, but beta R appeared later in post-natal development and was highly enriched in cerebellum in contrast to the broad regional distribution of beta G-spectrin. beta-Spectrins are likely to perform related but distinct functions, with beta G in a general, constitutive role and beta R-spectrin involved in more specialized activities of differentiated cells.

Amino Acid Sequence↗

PubMed2005

[Structural, functional and genetic aspects of peroxisome biogenesis].

Intracellular organelles, peroxisomes, occur in cells of most eukaryotic species. Human severe congenital disorders are associated with defective assembly and functioning of peroxisomes, which partly explains the attention of researchers paid to peroxisome biogenesis. It has been shown that peroxisomes are involved in the realization of eukaryotic developmental programs (in particular, neuroblast differentiation and postembryonic development). Cytobiochemical and electron-microscopic studies of mutations involving peroxisomes showed that the primary role in peroxisome biogenesis is played by synthesis of proteins (peroxins) and their transport and incorporation into peroxisome membranes. More than 30 peroxin-encoding genes have been examined. These genes are synthesized on free polysomes and transported into peroxisomes by means of specific signaling peptides, PTS1, PTS2, and PTS3. The import of matrix proteins depends on at least two shuttle receptor proteins, Pex5p and Pex7p. Some proteins regulating peroxisome proliferation in cells have been identified.

Animals↗

PubMedDate not supplied

[Neuroendocrine effect of sex hormones].

The paper provides a generalization of data and the results of own experiments on influence ovarian steroids on the hypothalamus and other brain areas related to reproduction. Ovarian hormones have widespread effects throughout the brain: on catecholaminergic neurons and serotonergic pathways and the basal forebrain cholinergic system, as well as the hipocampus, spinal cord, nigrostriatal and mesolimbic system, in addition to glial cells and blood-brain barrier. The widespread influences of these various neuronal systems ovarian steroids have measurable effects on mood and affect as well as on cognition, with implications for dementia. There are developmentally programmed sex differenced in hippocampal structure that may help to explain differences in the strategies which male and female rats use to solve spatial navigation problems. The multiple sites and mechanisms of estrogen action in brain underlie a variety of importants effects on cognitive and other brain functions--coordination of movement, pain, affective state, as well as possible protection in Alzheimer's disease. Estrogen withdrawal after natural or surgical menopause can lead to a host of changes in brain function and behavior.

Affect↗

PubMed1992

Four sarcomeric myosin heavy chain genes are expressed by human fetal skeletal muscle cells differentiating in culture.

Expression of four sarcomeric myosin heavy chain (MHC) genes was examined in continuously passaged human fetal (18-22 week) skeletal myoblasts and in myoblasts induced to differentiate by low mitogen medium. Although embryonic MHC mRNA predominated at all time points following induction, three additional MHC genes were expressed at lower levels. These consisted of perinatal, slow, and fast skeletal MHC genes. Temporal regulation of MHC gene expression was observed. In myoblasts and early induced cultures, embryonic and fast transcripts were detected, accompanied in later induced cultures by the accumulation of perinatal and slow MHC transcripts. In situ hybridization analysis of uninduced cells revealed that sarcomeric MHC transcripts originated from a small population of spontaneously fused multinucleated cells. Taken together, these observations demonstrate that human fetal myoblasts induced to differentiate in culture execute a developmental program that includes temporally regulated expression of four distinct sarcomeric MHC genes.

Base Sequence↗

PubMed2005

The impact of maternal protein malnutrition on pre-weaning skeletal and visceral organ growth in neonatal offspring of Rattus norvegicus.

Most studies of malnutrition focus on adult size, or limited durations of malnutrition. Little is known about the impact of life-long maternal malnutrition on young, pre-weaning offspring, in part because working with such infants is difficult. We created a maternal generation of malnourished dams by feeding female Sprague-Dawley rats, from weaning, either a control diet high in protein (CT) or an isocaloric low protein diet (LPT). The offspring of matings between these dams and control fathers were weighed daily and radiographed three times before sacrifice at 22d, when several visceral organs and muscles were dissected out and weighed. We compared lengths of craniofacial and limb bones, and organ and muscle weights, between the two diet treatments. Allometric cancellation was used to assess integration of growth among organs and muscles. The offspring of LPT dams had body, organ and muscle weights smaller than the offspring of CT dams. When scaled to body mass, some organs of the LPT offspring were relatively larger. Although the CT offspring skeletons were significantly larger than the LPT skeletons, considerable variation existed in the patterns of growth between the two treatments. The CT offspring had a higher level of correlation among muscles, and most organs, than did the offspring of LPT dams. The organs that did maintain a correlation in growth, or linkage, were pairs of organs more likely to be protected (heart-lung or eye-brain) from the insult of protein malnutrition. The ability to protect some organs may be the result of their tighter developmental program, one that is more resistant to differences in available nutrition.

Animals↗

PubMed2005

Natural selection and the conditions for existence: representational vs. conditional teleology in biological explanation.

Human intentional action, including the design and use of artifacts, involves the prior mental representation of the goal (end) and the means to achieve that goal. This representation is part of the efficient cause of the action, and thus can be used to explain both the action and the achievement of the end. This is intentional teleological explanation. More generally, teleological explanation that depends on the real existence of a representation of the goal (and the means to achieve it) can be called representational teleological explanation. Such explanations in biology can involve both external representations (e.g., ideas in the mind of God) and internal representations (souls, vital powers, entelechies, developmental programs, etc.). However, another type of explanation of intentional action (or any other process) is possible. Given that an action achieving a result occurs, the action can be explained as fulfilling the necessary conditions (means) for that result (end), and, reciprocally, the result explained by the occurrence of those necessary conditions. This is conditional teleological explanation. For organisms, natural selection is often understood metaphorically as the designer, intentionally constructing them for certain ends. Unfortunately, this metaphor is often taken rather too literally, because it has been difficult to conceive of another way to relate natural selection to the process of evolution. I argue that combining a conditional teleological explanation of organisms and of evolution provides such an alternative. This conditional teleology can be grounded in existence or survival. Given that an organism exists, we can explain its existence by the occurrence of the necessary conditions for that existence. This principle of the 'conditions for existence' was introduced by Georges Cuvier in 1800, and provides a valid, conditional teleological method for explaining organismal structure and behavior. From an evolutionary perspective, the conditions for existence are the range of boundary conditions within which the evolutionary process must occur. Moreover, evolutionary change itself can be subjected to conditional teleological explanation, because natural selection theory is primarily a theory about the relation between the conditions for the existence of organisms and the conditions for the existence of traits in populations. I show that failure to distinguish representational from conditional teleological explanation has confused previous attempts to clarify the relation of teleology to biology.

Adaptation, Biological↗

PubMed2006

[Promotion of the systematization of consistent education for medical technologists].

Although only about 35 years have passed since the birth of medical technology, marked advances have been made in the clinical laboratory science field. However, the educational system for technologists attached importance only to the learning of techniques for a long period because special training schools primarily provided medical technologist education. With the passing of time, the need for advanced knowledge has increased, and a plan to change the education system for medical technologists to 4-year colleges was evaluated. In 1989, the Course of Laboratory Sciences as a 4-year system for medical technologist education was established in the Department of Medicine, Tokyo Medical & Dental University. The Doctoral Course of Graduate School (first term) was established in 1993 and the Doctoral Course of Graduate School(second term) in 1995. In 2001, these courses formed a graduate university as the Division of Biomedical Laboratory Sciences, the Graduate School of Allied Health Sciences. Thus, a consistent educational system for medical technologists was established. By March 2005, about 500 students had graduated from this division. Based on this experience, we produced a 4-stage developmental program and provide an advanced educational system for the promotion of the systematization of consistent medical technologist education.

Education, Graduate↗

PubMed2006

[Impairment of the ubiquitin-proteasome system and neurodegeneration].

There are growing lines of evidence addressing the importance of the ubiquitin-proteasome system (UPS) that catalyzes various biological reactions rapidly, methodically, exhaustively, and unidirectionally. UPS is responsible for a diverse array of biologically important cellular processes, such as cell-cycle progression, signaling cascades and developmental programs. This system is also involved in the protein quality control, which maintains the homeostasis of the cell. Of particular interest is that UPS provides a clue for understanding of the molecular mechanisms underlying various neurodegenerative diseases. In the last decade, we witnessed a tremendous progress in uncovering the mechanisms of Parkinson's disease (PD). Of the several genes that can cause familial PD, parkin, the causative gene of autosomal recessive juvenile parkinsonism (AR-JP), is of a special interest because it encodes an ubiquitin-protein ligase, which covalently attaches ubiquitin to target proteins, designating them for destruction by the proteasome (a eukaryotic ATP-dependent protease complex). This review summarizes recent studies on the UPS pathway with a special reference to parkin, focusing on how parkin is linked to the pathogenesis of AR-JP.

Humans↗

PubMed2006

[Dynamics of morphofunctional organization and developmental potential of mouse embryos in the state of "two-cell block in vitro"].

Vital observation in combination with electron microscopy and immunocytochemistry was used for studying structural organization and developmental potential of BALB/c mouse embryos after cleavage cessation at a two cell stage caused by the "two-cell block in vitro" phenomenon. Modification of structure and viability of embryos was followed for 2 days from the time of cleavage arrest. Several hours before cleavage arrest, changes in mitochondrian distribution were noticed in embryos, no other disturbances in structural organization of blastomeres being obvious. Embryos, whose development was arrested for 24 h, remained viable and demonstrated some morphological changes similar to those seen in normally developing embryos of the same age. Towards the end of a 48 h block period some embryos died, the surviving embryos remained morphologically intact and metabolically active. At the same time, the nuclei of the latter frequently displayed chromatin condensation near the nuclear membrane, which is similar to the pattern of chromatin reorganization in the nuclei of early apoptotic cells. Our results support a concept on the "two-cell block in vitro" phenomenon as a specific functional state of embryos, and well compare with data on a partial realization by blocked embryos of the developmental program.

Animals↗

PubMedDate not supplied

[Drosophila genes that encode LIM-domain containing proteins: their organization, functions, and interactions].

Diverse sets of developmental programs including cytoskeleton organization, cell lineage specification, muscle and neuron differentiation, limb and eye formation, imaginal disk development are controlled by LIM-homeobox genes encoding LIM-homeodomain (LIM-HD) transcription factors. LIM-domains are known as adaptors and functional modifiers of the protein-protein interactions and of the specific contacts between the members of functional complexes mediating activation of some constitutive proteins. Primary structure of LIM-HD proteins is remarkably evolutionary conserved in vertebrates and invertebrates. Though the genome size of Drosophila is about 5 % of the mammal genome the majority of its gene families and signaling pathways are similar to those of the mammals. There are some well known LIM-domain-containing proteins in Drosophila: Arrowhead, Apterous, Islet, dLim and Lim3 transcription factors; DLMO and Prickle proteins, as well as Chip, RLIM, Ssdp cofactors that modulate the LIM-HD function. Drosophila is a unique model system to analyze genetic interactions and transcription complexes in vivo. Genetic and molecular approaches including isolation of extragenic supressors of mutations in LIM-HD proteins may be used for identification of target genes which interact directly with LIM-HD proteins and that are necessary for specification of cell identity.

Animals↗

PubMed1991

The murine W/c-kit and Steel loci and the control of hematopoiesis.

The experiments summarized here indicate that germ-line mutations in either the c-kit receptor tyrosine kinase (W mutants) or its ligand (Sl) lead to profound and pleiotropic developmental defects, including abnormalities within the hematopoietic system. These observations parallel findings in other developmental systems, notably the fruit fly Drosophila, that receptor tyrosine kinases play key roles in the determination of cell fate and the elaboration of developmental programs. Thus, it appears that the processes of hematopoiesis, melanogenesis, and gametogenesis in mammals involve a similar strategy to that used in other species for transmitting and receiving positional cues during development. Finally, it is interesting to note that what began as an attempt to understand the molecular basis of coat color mutations in the mouse has led to the identification of a key cell-signalling pathway in the development of at least three cell lineages in mammals. Further analysis of the W/Sl pathway should provide a more complete understanding of the early events in hematopoiesis, and may also lead to novel therapeutic applications involving the protein product of the Sl locus.

Animals↗