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PubMed2001

Identification of two distinct types of multipotent neural precursors that appear sequentially during CNS development.

Epidermal growth factor (EGF) and fibroblast growth factor (FGF)-2 control neural stem cell proliferation in vitro and the formation of neurospheres. Neurospheres contain precursors that respond to both EGF and FGF-2 (E/F cells). E/F cells appear to originate from cells that initially respond to FGF-2 only but undergo a transition in growth factor responsiveness during in vitro culturing. It is unclear whether a similar change in growth factor responsiveness of multipotent precursors takes place in vivo and how this may affect neural precursor properties. Here I provide evidence that FGF-2-responsive precursors and E/F cells appear sequentially during CNS development. This transition from the early precursors (FGF-2-responsive cells) to the late precursors (E/F cells) takes place between E14 and E18. The two types of precursors are morphologically and antigenically distinct. E/F cells are very large and show strong nestin immunoreactivity. Thus the putative neurosphere-forming E/F cells are present in vivo and their generation is developmentally programmed. Their unique morphology may provide a basis for their isolation.

Age Factors↗

PubMedDate not supplied

How a child builds its brain: some lessons from animal studies of neural plasticity.

Although the potential vulnerability of children's brain development is generally recognized, relatively little is known about the timing, resiliency, or mechanisms involved. While animal research should be applied only cautiously to human policy, some findings do have important clinical implications. This paper briefly reviews animal studies demonstrating the effects of experience on brain structure. Contemporary theories emphasize the self-organizing potential of brain structure, particularly regions that seem to have evolved for the purpose of storing information. We emphasize three major findings: (1) many regions of the brain are responsive to experience, but they differ in the types of information stored and in their developmental timing. (2) One type of plasticity is typically embedded in a developmental program, and it requires appropriate timing and quality of the information stored for the animal's development to be normal. (3) Another category of plasticity stores information that is idiosyncratic and unpredictable, but is often useful for species such as humans that learn throughout their life span. We therefore expect that some aspects of human brain development use the first type of plasticity and that abnormal experience or deprivation may cause lasting harm to brain and behavior. However, because the other type of plasticity lasts a lifetime, efforts such as psychotherapy or social interventions may help heal a wounded brain.

Animals↗

PubMed1996

Normal and leukemic human stem cells assayed in SCID mice.

Understanding the processes that regulate the developmental program of normal stem cells and those that initiate proliferative diseases such as leukemia remains one of the major challenges in biology. Progress to address these major questions in the human hematopoietic system have been hampered, until recently, by the lack of in-vivo assays for normal and leukemic stem cells. The recent development of methods to transplant normal and leukemic human hematopoietic cells into immune-deficient mice provides an important approach to identify, characterize and purify stem cells. This review will focus on the development of assays for normal and leukemic human stem cells and on the new insights these assays are beginning to provide on the organization of the human stem cell hierarchy and mechanisms of leukemogenesis.

Acute Disease↗

PubMed2006

Integrating the diagnosis of childhood malignancies.

Significant progress has been made in understanding the molecular basis of pediatric malignancies. Mechanisms of pediatric acute leukemia induction include hyperdiploidy, aberrant expression of proto-oncogenes, and activation of transcription factors or kinases by aberrant fusion genes. Molecular analysis of these alterations has facilitated the recognition of distinct groups with different sensitivity to therapy, and identified potential targets for antileukemic agents. Similar analysis of pediatric soft tissue and bone tumors also resulted in the identification of specific fusion genes, and their characterization has contributed greatly to understand their biology. Molecular assays for these rearrangements have become important tools in classifying these tumors, providing important prognostic data. However, the understanding of mechanisms involved in the pathogenesis of many other pediatric malignancies, including some embryonal tumors--believed to arise due to perturbation of the normal developmental program--is still vastly incomplete. The Department of Pathology at Texas Children's Hospital is one of the Children's Oncology Group (COG) reference centers for pediatric liver tumors. We have been particularly interested in the biology of hepatoblastoma, the most common type of pediatric liver tumor. Although a number of cytogenetic and molecular abnormalities have been described for this type of embryonal tumor, its pathogenesis is still poorly understood. In an attempt to explore the role of different signaling pathways in this disease, we analyzed the expression patterns of different histologic subtypes of hepatoblastoma using cDNA microarray analysis, qualitative reverse transcription, polymerase chain reaction (QRT-PCR), and immunohistochemistry. Wnt signaling pathway, critical both in development and in neoplasia, appears to be particularly relevant in these tumors. Mutations of the beta-catenin gene are present in over 90% of hepatoblastomas, leading to activating transcription of a number of target genes. The pattern of beta-catenin expression and type of mutation in groups of tumors are crucial to understand the corresponding differences in their gene expression profiles. Our findings are consistent with a relationship between poor histologic phenotype and beta-catenin activation, indicating the potential utility of targeted gene expression assays to identify molecular events related to the pathogenesis and prognosis of hepatoblastomas. Integration of clinical, morphologic, phenotypic, cytogenetic, and molecular data has become the basis of novel prognostic prediction and therapeutic strategies in pediatric leukemia. Similarly, integration of new genetic and molecular data with clinical, and other diagnostic information will be crucial for accurate classification of pediatric tumors, risk stratification, and successful development of new therapies for pediatric oncologic patients.

Child↗

PubMed2003

Hypoxia and lung branching morphogenesis.

Morphogens, growth factors and extracellular matrix (ECM) components modulate early lung branching, and have been studied extensively both in vivo and in vitro. In vitro studies have been particularly useful, because tissue can be manipulated either chemically or mechanically. For the most part, such studies have been conducted at ambient oxygen tensions, despite the fact that the fetus develops in a low oxygen environment. Since oxygen tension regulates the expression of various growth factors, adhesion molecules and their receptors, we investigated whether the low oxygen environment of the fetus contributes towards lung branching morphogenesis by affecting one or more these mediators. Using an established fetal lung explant model, we demonstrated that in comparison to tissues cultured at ambient oxygen concentration (21% O2), fetal lung explants cultured at 3% O2 show increases in terminal branching and cellular proliferation, and they display appropriate proximal to distal differentiation. To investigate the factor(s) mediating the induction of lung branching morphogenesis and differentiation by fetal oxygen tension, we focused on matrix metalloproteinases (MMPs), a group of zinc-dependent enzymes that modify ECM structure and function. Our results reveal that hypoxia suppresses MMP activity, leading to the accumulation of specific ECM components, including tenascin-C (TN-C), that act to stimulate lung branching. These studies demonstrate that low oxygen in the setting of the developing lung positively regulates lung branching morphogenesis, and suggest that the pathologic responses to low oxygen in the adult lung reflect a dysregulation of this lung developmental program.

Animals↗

PubMed1996

Light-dependent developmental control of rbcS gene expression in epidermal cells of maize leaves.

Regulatory elements of the maize rbcS-m3 gene (a member of the family of genes encoding the small subunit of ribulose bisphosphate carboxylase) that are sufficient for expression of the beta-glucuronidase (gusA) gene in photosynthetic tissue lead to relatively weak expression of the reporter gene in epidermal cells of green maize leaves when delivered by ballistic gene transfer methods. However, epidermal cells of white, immature segments of maize leaf bases express the same reporter gene strongly. Morphologically, these epidermal cells look undifferentiated and are uniform in size and shape. When cultured for seven days on Murashige-Skoog medium [18], exised leaf base segments expand two-to threefold, and epidermal and guard cells differentiate and mature, regardless of whether or not the tissue is illuminated. Epidermal cells that differentiate in darkness continue to have the capacity to express the rbcS-m3::gusA reporter gene strongly. However, if the leaf base segments are illuminated after four to five days of expansion in darkness, but not before, these more mature epidermal cells are largely unable to express the same gene. That is, they acquire the characteristics of epidermal cells of green maize leaves with regard to expressing the rbcS-m3 reporter gene after undergoing a developmental program (in light or darkness) in vitro and after being exposed to light. White light but not red is effective. Suppression of expression in maize epidermal cells requires different rbcS-m3 sequences than in mesophyll cells [31].

Chloroplasts↗

PubMed1995

Intermediate filament proteins increase during chronic stimulation of skeletal muscle.

Chronic low-frequency electrical stimulation of rabbit fast-twitch skeletal muscle induces increased levels of two intermediate filament proteins, desmin and vimentin, during the first 3 weeks of stimulation. These increases occur over the same timecourse as reported shifts in alpha-actinin expression and increased Z-disc width, but precede the fast-to-slow shifts in contractile proteins, which have been described by others. Desmin and vimentin levels increase during the first 2 weeks of stimulation, at which time the increase in desmin appears to plateau while vimentin continues to increase significantly through 3 weeks of stimulation. Absolute amounts of vimentin are lower than desmin at all time points, however increases in desmin and vimentin levels are strongly correlated during the stimulation period, suggesting that the two proteins are coordinately increased during the initial phases of muscle transformation. We suggest that rapid increases in the expression of intermediate filament proteins, which coincide with alterations in Z-disc structure, may indicate a fortification of the force-bearing ultrastructure of the muscle fibre in response to the increased activity that is induced by stimulation. The presence of vimentin and elevated levels of desmin expression suggest that mature skeletal muscle reverts toward a developmental program of intermediate filament protein expression during fast-to-slow transformation.

Actins↗

PubMed1995

Identification of two Drosophila TGF-beta family members in the grasshopper Schistocerca americana.

Intercellular signaling molecules of the transforming growth factor-beta (TGF-beta) superfamily are required for pattern formation in many multicellular organisms. The decapentaplegic (dpp) gene of Drosophila melanogaster has several developmental roles. To improve our understanding of the evolutionary diversification of this large family we identified dpp in the grasshopper Schistocerca americana. S. americana diverged from D. melanogaster approximately 350 million years ago, utilizes a distinct developmental program, and has a 60-fold-larger genome than D. melanogaster. Our analyses indicate a single dpp locus in D. melanogaster and S. americana, suggesting that dpp copy number does not correlate with increasing genome size. Another TGF-beta superfamily member, the D. melanogaster gene 60A, is also present in only one copy in each species. Comparison of homologous sequences from D. melanogaster, S. americana, and H. sapiens, representing roughly 900 million years of evolutionary distance, reveals significant constraint on sequence divergence for both dpp and 60A. In the signaling portion of the dpp protein, the amino acid identity between these species exceeds 74%. Our results for the TGF-beta superfamily are consistent with current hypotheses describing gene duplication and diversification as a frequent response to high levels of selective pressure on individual family members.

Amino Acid Sequence↗

PubMed1995

Comparison of human and mouse T-cell receptor variable gene segment subfamilies.

Like the immunoglobulin Igh-V and Igk-V gene families, the human or mouse TCRV gene families may be grouped into subfamilies displaying > 75% nucleic acid sequence similarity among their members. Systematic interspecies sequence comparisons reveal that most mouse Tcr-V subfamilies exhibit clear homology to human TCRV subfamilies (> 60% amino acid sequence similarity). Homologous pairs of TCRV genes in mice and humans show higher sequence similarity than TCRV genes from different subfamilies within either species, indicating transspecies evolution of TCRV genes. Mouse and human homologues show conservation of their relative map order, particularly in the 3' region and a similar sequential and developmentally programmed expression. When the V regions from both species were analyzed together, local length differences and conserved residues in the loop regions were revealed, characteristic of each of the four TCRV families.

Alleles↗

PubMed1992

Light and electron microscopic morphology of the temporomandibular joint in growing and mature crab-eating monkeys (Macaca fascicularis): the condylar calcified cartilage.

In an attempt to show maturational alterations in the calcified cartilage, mandibular condyles of four growing and four adult male monkeys (Macaca fascicularis) were studied using light microscopy as well as transmission and scanning electron microscopy. All specimens were initially fixed by perfusion in the presence of ruthenium red. For examination of the hard tissue surfaces in the scanning electron microscope, uncalcified tissues were removed with sodium hypochlorite. In growing animals, almost the entire hard tissue surface in the joint region of the condyle was formed by calcified cartilage, while in adult animals, calcified cartilage was confined to load-bearing regions. In growing animals, the appearance of the calcified cartilage surface suggested a continuously advancing mineralizing front similar to that seen in the epiphyseal plate. Chondrocytes mostly exhibited a terminal stage of hypertrophy, and seemed to die and get lost through vascular invasion and subsequent endochondral ossification. In adult animals, most of the calcified cartilage surface appeared comparatively stable, and resembled the tidemark of articular cartilage. Chondrocytes were usually small and appeared viable. However, on the adult condyles, there were always circumscribed islands where chondrocytes and the pattern of mineralization resembled those seen in growing animals. In these regions, prominent chondroclastic activity indicated extensive articular remodelling. These observations suggest that at the end of somatic growth, condylar calcified cartilage undergoes considerable maturation from a type reminiscent of hyaline growth cartilage to a type resembling articular cartilage. Concomitantly, chondrocytes appear to change their developmental program, in that they stop enlarging and lose their commitment to death. However, they may be able to retain, or switch back to, a more immature stage, in case there is need for extensive articular remodelling.

Animals↗

PubMed1992

Diversity of T-cell receptor alpha gene transcripts in the newborn and adult periphery.

Recent studies have demonstrated that the diversity of T-cell receptor alpha (Tcra) gene expression may be confined by a developmental program for gene rearrangement. To examine the effect of age on Tcra gene usage in peripheral tissues, a comparison of Tcr transcripts from newborn and adult mouse splenocytes was made. RNA was first isolated from the spleens of newborn (within five days from birth) and adult B10.BR mice. The polymerase chain reaction was then used to assess the presence of Tcra-V1, Tcra-V2, and Tcra-V3 gene sequences within the two RNA pools. The Tcra-V2 transcript was frequent in both newborn and adult populations and was therefore selected for sequencing analyses, by which V-gene family member and J gene usage could be delineated. Forty-one sequences were obtained, demonstrating Tcra-V2 gene family structure in the B10.BR mouse. Six family members were identified, of which four were new. Although there were differences in gene usage between newborn and adult animals, some junctional diversity added to the repertoire of both populations. A striking feature of V-J joining, as illustrated by this study, was the restriction of combinations based on the J gene location within the Tcra locus. The Tcra-V2 gene of dominant expression in the newborn (B10.BR.6) rearranged exclusively with the 30 most 5' Tcra-J genes. The Tcra-V2 gene of dominant expression at the adult stage (B10.BR.1) rearranged exclusively with the 21 most 3' Tcra-J genes in the locus. Thus, V-J combinatorial diversity was restricted in both newborn and adult mice, yielding a trend from 5'-3' Tcra-J gene usage with age. Inherent restrictions in V-J combinations should now be considered with regard to antigen responsiveness, particularly in the young animal. Qualitative restrictions in Tcr repertoire, compounding low T-cell numbers in peripheral tissues, may well contribute to functional voids and immunodeficiencies in early life.

Age Factors↗

PubMed1980

Role of innervation on the embryonic development of skeletal muscle.

The extent to which the motor innervation regulates the embryonic development of skeletal muscle was investigated by comparing changes in normal, aneural, and paralyzed superior oblique muscle of the duck embryo. The muscle was made aneural by permanently destroying the trochlear motor neurons with electrocautery on day 7, i.e., three days prior to innervation. Embryos were paralyzed by daily application of alpha-bungarotoxin onto the chorioallantoic membrane from day 10 onwards. The differentiation of myoblasts and myotubes in the aneural muscle was severely affected and did not progress to the myofiber stage. A mass of dead cells in the aneural muscle was replaced by connective tissue. Although the differentiation of myoblasts and myotubes was also retarded in the paralyzed muscle, numerous muscle cells progressed to the myofiber stage. Neuromuscular junctions of normal ultrastructure were seen in all paralyzed muscles. Degeneration of some cells in the paralyzed muscle occurred but there was no evidence of a massive wave of cell death similar to that observed in the aneural muscle. These observations suggest that both the trophic factors from the nerve and the nerve-evoked muscle activity are essential for the execution of the developmental program of the muscle. Trophic factors may play a larger role in differentiation, and maintenance of the muscle than muscle activity.

Animals↗

PubMed1983

Maturation of monoamine neurotransmitters and receptors in cat occipital cortex during postnatal critical period.

The postnatal development of monoamine levels and receptors in the occipital cortex of the cat has been investigated using neurochemical techniques. The endogenous catecholamines (noradrenaline and dopamine) gradually increased with age, displaying an about 12-13-fold increase in their concentration from the newborn to the adult stage. 3H-dihydroalprendol (beta-adrenoceptor ligand) binding showed a rapid increase from the low value (25% of the adult value) at birth, peaking at the age of 7-9 weeks with a value of about 150% of adults. The beta-adrenoceptor binding stayed relatively constant at adult value from the age of 11 weeks throughout. Endogenous 5-hydroxytryptamine levels were at birth about 20% of the adult value and thereafter rapidly increased, peaking at the age of 3-5 weeks when it reached the adult value. Between the age of 7-13 weeks the 5-hydroxytryptamine level was about 50-60% of adult. The developmental pattern for 3H-5-hydroxytryptamine binding was similar to that of endogenous 5-hydroxytryptamine, although with certain quantitative differences. The 3H-5-hydroxytryptamine receptor binding showed a steep peak at an age of about 4 weeks when the binding was about 300% of the adult value. Thereafter the binding gradually levelled off in adulthood. Similar results were obtained in the frontal cortex, except for some quantitative differences. The present results thus indicate that both noradrenaline and 5-hydroxytryptamine nerve terminals develop, largely independent of their postsynaptic receptors, probably due to different developmental programs regulating their expression. The development of monoamine receptors appear to precede that of their nerve terminals. The different roles played by beta-adrenoceptors and 5-hydroxytryptamine receptors for the maturation of occipital cortex during postnatal critical period were discussed.

Animals↗

PubMed1986

High susceptibility for diploidy in ovulated oocytes from XO mice.

Adult female mice of the "sensitive" NMRI/Han strain ovulate diploid oocytes after gonadotropin treatment. Other mouse strains are "non-sensitive" with respect to the ovulation of such diploid oocytes. In this study we combined the impaired ovarian situation in the XO karyotype with the trait "diploidy", which is determined genetically, by mating Ta/O (Ta = Tabby) females of C3H X 101 background to males of the NMRI/Han strain. The adult female F1 hybrids were stimulated to ovulation by gonadotropins and identified by their karyotype (XX or XO). The cytogenetic analysis of ovulated oocytes revealed a low level of diploidy in the XX littermates (1.0%), but a very high level in females with the XO karyotype (24.6%). All of the XO females ovulated at least one diploid oocyte. We suggest that it is the XO status which drastically impairs meiosis I in our "gonadotropin-sensitive" F1 females due to (1) alterations of the developmental program within the oocyte, (2) a disturbed communication between oocyte and follicle, (3) a preferential maturation and ovulation of "follicles at risk", or (4) an exceptional recruitment of many such follicles, by, e.g., a premature responsiveness to gonadotropins in our XO females. An interdependence of several such mechanisms is possible.

Animals↗

PubMed1995

Retinal ellipsosomes: morphology, development, identification, and comparison with oil droplets.

We report some unique features of retinal cone ellipsosomes in mountain-stream teleosts. They have also been compared with oil droplets occurring predominantly in many reptilian and avian retinas. Ontogenetically, ellipsosome differentiation from ellipsoidal mitochondria occurs with advanced eye growth (diameter > 1 mm). In juvenile loaches, they arise almost simultaneously in the dorsal and ventral retina, whereas in cyprinids, they appear first dorsally in bottom-dwelling early juveniles (approximate age 3-4 months), and then in the ventral retina in migratory late juveniles (eye diameter > 4 mm, approximate age 2 years). The significance of the pattern of ontogeny of ellipsosomes in these stream fishes is discussed in relation to their utilization of a complex habitat during life. All adult cones possess conspicuous ellipsosomes. Histochemically, they react strongly with phosphotungstic-acid hematoxylin, a dye specific for proteins, whereas oil droplets refuse to do so (studied in turtle and pigeon). This reflects a major chemical difference between the two types of globules. Since ellipsosomes are present in the double cone accessory unit (which in higher vertebrates lacks an oil droplet) and since they appear late ontogenetically during advanced eye growth, they cannot be related to oil droplets, which have an embryonic developmental program.

Animals↗

PubMed1985

The giant (gt) mutants of Drosophila melanogaster alter DNA metabolism.

Abnormalities in DNA metabolism have been found in third-instar females of Drosophila melanogaster that are heteroallelic or homoallelic for X-chromosomal giant (gt) mutations. Analysis of DNA metabolism in larval brain ganglia was carried out using alkaline sucrose gradient centrifugation, incorporation assays and a neutral filter elution assay. These analyses show that gt stocks synthesize DNA of a reduced molecular weight, have an unusually high frequency of spontaneous single and double-strand breaks, and exhibit a reduction in the normal inhibition of DNA synthesis following treatment with UV and the carcinogen AAAF. These phenomena are not associated with a defect in the repair of X-ray induced DNA breaks nor are they accompanied by any alterations in chromosome stability. Analysis of homozygous 1(2)gl larvae also reveal that these phenomena are specific to the gt locus and are thus not attributable solely to an extended developmental program. These findings strengthen the suggestion that the genetic instability associated with gt is related to perturbations in chromosome metabolism (Green 1982).

Acetoxyacetylaminofluorene↗

PubMed1985

The role of visual experience in the development of cat striate cortex.

By the third postnatal week, intrinsic developmental programs have established a framework within the cat visual system; this will be used to guide the course of subsequent experience-dependent development. Key elements in this framework are precociously mature cells in visual cortex area 17. These orientation-selective cells are predominantly first-order neurons, they are concentrated in layers IV and VI of area 17, most of them are activated monocularly, many may receive their direct excitatory input from lateral geniculate nucleus X cells, and the distribution of their preferred orientations is biased toward horizontal and vertical. Between the third and the sixth postnatal week, most of the remaining cells in area 17 develop orientation selectivity; this extension of orientation selectivity is blocked or delayed if kittens are deprived of normal patterned visual stimulation. Furthermore, exposure to a limited range of stimulus orientations can lead to an increase in the proportion of orientation-selective cells, and the range of orientation preferences that the cells acquire is restricted by the range of orientations to which the animal is exposed. This occurs with no apparent change in the physiology or morphology of intrinsically selective area 17 cells. Thus selective exposure may have its effect by influencing the connections between the intrinsically selective cells and higher-order neurons in area 17. Experience-dependent changes in the visual system may function to "fine-tune" sensory processing and thus optimize the system's response to the dominant features of the environment. This experience-dependent process could help the young animal to focus its "attention" on those features of its environment that are critical to its survival.

Animals↗

PubMed1985

Temperature-sensitive non-fusing myoblast variant and spontaneous revertant: isolation and characterization.

A stable, temperature-sensitive, non-fusing variant of the L6 rat myoblast cell line has been isolated following mild EMS-induced mutagenesis. At the permissive temperature (37 degrees C), the growth characteristics and developmental pattern of the tsA1 variant are essentially identical to those of the parental L6D0 line at either 37 degrees C or 40 degrees C. At the nonpermissive temperature (40 degrees C), the tsA1 variant grows normally but does not align, fuse, or synthesize detectable amounts of beta-tropomyosin or myosin LC2. A peptide corresponding to myosin LClemb is barely detectable. The temperature-sensitive period spans the interval from 4 to 72 h post-plating with a midpoint at approximately 40 h. Under standard culture conditions, commitment to terminal differentiation occurs between days 3 and 4, and alignment and fusion begin on days 4 and 5, respectively. Thus, the temperature-sensitive event occurs very early in the L6 developmental program. A spontaneous revertant of the temperature-sensitive phenotype (tsA1 [R3]) exhibits recovery of the capacities to align, fuse, and synthesize the repertoire of muscle-specific proteins, suggesting that a single pleiotropic mutation in the tsA1 variant may regulate several stages in L6 myogenesis.

Animals↗