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Biomedical subjects

K Muneoka

Publications and source records attributed to K Muneoka.

At least 19 recordsLinked to original sources
PubMed2000

Influence of FGF4 on digit morphogenesis during limb development in the mouse.

Much of what we currently know about digit morphogenesis during limb development is deduced from embryonic studies in the chick. In this study, we used ex utero surgical procedures to study digit morphogenesis during mouse embryogenesis. Our studies reveal some similarities; however, we have found considerable differences in how the chick and the mouse autopods respond to experimentation. First, we are not able to induce ectopic digit formation from interdigital cells as a result of wounding or TGFbeta-1 application in the mouse, in contrast to what is observed in the chick. Second, FGF4, which inhibits the formation of ectopic digits in the chick, induces a digit bifurcation response in the mouse. We demonstrate with cell marking studies that this bifurcation response results from a reorganization of the prechondrogenic tip of the digit rudiment. The FGF4 effect on digit morphogenesis correlates with changes in the expression of a number of genes, including Msx1, Igf2, and the posterior members of the HoxD cluster. In addition, the bifurcation response is digit-specific, being restricted to digit IV. We propose that FGF4 is an endogenous signal essential for skeletal branching morphogenesis in the mouse. This work stresses the existence of major differences between the chick and the mouse in how digit morphogenesis is regulated and is thus consistent with the view that vertebrate digit evolution is a relatively recent event. Finally, we discuss the relationship between the digit IV bifurcation restriction and the placement of the metapterygial axis in the evolution of the tetrapod limb.

Animals↗
PubMed2000

Evaluation of biologically based dose-response modeling for developmental toxicity: a workshop report.

Biologically based dose-response (BBDR) modeling represents a novel approach for quantitative assessment of health risk by incorporating pharmacokinetic and pharmacodynamic characteristics of a chemical and by relating the immediate cellular responses to a cascade of aberrant biological actions that leads to detectable adverse outcomes. The quantitative relationship of each of the intervening events can be described in mathematical forms that are amenable for adjustment and extrapolation over a range of doses and across species. A team of investigators at the Reproductive Toxicology Division of the U.S. Environmental Protection Agency has explored the feasibility of BBDR modeling by examining the developmental toxicity of a known teratogen, 5-fluorouracil. A panel of researchers from academic and industrial laboratories, biomathematical modelers, and risk assessment scientists was convened in a workshop to evaluate the approaches undertaken by the EPA team and to discuss the future prospects of BBDR modeling. This report summarizes the lessons learned from one approach to BBDR modeling and comments from the panelists: while it is possible to incorporate mechanistic information into quantitative dose-response models for the assessment of health risks, the process is enormously data-intensive and costly; in addition, the confidence of the model is directly proportional to our current understanding of basic biology and can be enhanced only through the ongoing novel discoveries. More importantly, the extent of "uncertainty" (inherent with the default assumptions associated with the NOAEL or benchmark approach) reducible by BBDR modeling requires further scrutiny and comparison.

Abnormalities, Drug-Induced↗
PubMed2000

Effects of neonatal melatonin administration on the extra-hypothalamic regions in rat brains: effects on the serotonergic system.

The effects of 100microg melatonin injection at postnatal day 5 (PD 5) on the development of the central serotonergic systems in male and female rats were investigated. The contents of serotonin (5-HT) and 5-hydroxy-3-indolacetic acid (5-HIAA) were measured in several extrahypothalamic regions at 3, 10 and 42 weeks of age. The neonatal melatonin administration increased both 5-HT and 5-HIAA levels in the striatum throughout the examined period. In the hippocampus, an increase in 5-HIAA contents by neonatal melatonin administration was found at 3 weeks but not 10 or 42 weeks of age. There were no significant differences in the effects of melatonin between male and female rats. These results indicated that exogenous melatonin administration during the early neonatal period influenced the development of the serotonergic systems in extrahypothalamic regions including the hippocampus and the striatum.

Animals↗
PubMed1999

Cell migration and chick limb development: chemotactic action of FGF-4 and the AER.

Experiments have been carried out to investigate the role of the apical ectodermal ridge (AER) and FGF-4 on the control of cell migration during limb bud morphogenesis. By coupling DiI cell labeling with ectopic implantation of FGF-4 microcarrier beads we have found that FGF-4 acts as a potent and specific chemoattractive agent for mesenchymal cells of the limb bud. The response to FGF-4 is dose dependent in both the number of cells stimulated to migrate and the distance migrated. The cell migration response to FGF-4 appears to be independent of the known inductive activity of FGF-4 on Shh gene expression. We investigated the role of the AER in controlling cell migration by characterizing the migration pattern of DiI-labeled subapical cells during normal limb outgrowth and following partial AER removal. Subapical cells within 75 micrometer of the AER migrate to make contact with the AER and are found intermingled with nonlabeled cells. Thus, the progress zone is dynamic with cells constantly altering their neighbor relationships during limb outgrowth. AER removal studies show that cell migration is AER dependent and that subapical cells redirect their path of migration toward a functional AER. These studies indicate that the AER has a chemoattractive function and regulates patterns of cell migration during limb outgrowth. Our results suggest that the chemoattractive activity of the AER is mediated in part by the production of FGF-4.

Animals↗
PubMed1999

Serotonin-induced platelet intracellular Ca2+ responses in untreated depressed patients and imipramine responders in remission.

BACKGROUND: Intracellular Ca2+ metabolism in platelets has been investigated as a peripheral marker of affective disorders. METHODS: We investigated the intracellular free Ca2+ concentration in platelets in both untreated depressed patients with no medications and patients in remission who were treated by imipramine (IMI) (IMI responders) using a Ca(2+)-sensitive fluorescent probe fura-2. RESULTS: The increases in intracellular free Ca2+ concentration in platelets induced by stimulation with serotonin (5-HT) ([Ca2+] delta) were significantly higher in both the untreated patients and the IMI responders compared with healthy controls; however, there were no significant differences in the basal Ca2+ levels in the platelets ([Ca2+]B) among the three groups. On the other hand, in the IMI responders, we observed positive correlations between the duration of the remission and [Ca2+]B, but not [Ca2+] delta. CONCLUSIONS: Our present data suggest that the enhancement of 5-HT2A-induced Ca2+ responses persisted after remission in depressed patients, and that the duration of the remission is a factor varying the intracellular basal Ca2+ levels.

Adult↗
PubMed1998

Electrolytes in erythrocytes of patients with depressive disorders.

The concentrations of calcium, sodium, potassium and magnesium in the erythrocytes of patients were measured in the active and remission phases of depressive disorders. Twelve patients in the active phase and 19 patients in remission with major depression were studied and compared with 20 age-matched healthy controls. Patients with major depression in both active and remission phases showed significantly lower calcium concentrations in the erythrocytes compared with controls, although no significant differences in sodium, potassium or magnesium concentrations were found among the three groups. In addition, no differences were found in the electrolyte concentrations between the active and remission phases in the same patients. This calcium concentration had no relationship to the age, gender, or medication drugs of the subjects. Low calcium concentrations were found in the erythrocytes of depressed patients, which may be a relevant marker for depression.

Adult↗
PubMed1998

Chronic imipramine administration amplifies the serotonin2A receptor-induced intracellular Ca2+ mobilization in C6 glioma cells through a calmodulin-dependent pathway.

In the present study, we examined whether chronic exposure of C6BU-1 cells to 100 nM of several different types of antidepressants directly influences serotonin2A (5-HT2A) receptor-stimulated intracellular Ca2+ mobilization. Imipramine, desipramine, clomipramine, and maprotiline amplified the 5-HT response at 48, but not at 2, h. Imipramine increased the maximum response to 5-HT without altering the EC50 of the dose-response curve. This effect was time dependent and cycloheximide blocked the maximal induction, suggesting an essential role for protein synthesis in this process. Previous exposure of the cells to thrombin or isoproterenol did not influence 5-HT2A receptor function and pretreatment with imipramine did not alter the thrombin- or bradykinin-induced Ca2+ mobilization, which indicates that the effects of imipramine appear to be specific to the 5-HT2A receptor. The effect of imipramine was potently suppressed by a calmodulin antagonist, W-13, in a dose-dependent manner. Furthermore, this amplified 5-HT response was blocked by KN-93, but not by H-7. Taken together, these results suggest that imipramine has a modulatory effect on the 5-HT2A receptor-coupled intracellular Ca2+ in C6 cells through a calmodulin-dependent pathway, possibly involving Ca2+/calmodulin kinase activation.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed1997

Prenatal nicotine exposure affects the development of the central serotonergic system as well as the dopaminergic system in rat offspring: involvement of route of drug administrations.

The present study was undertaken to examine the effects of prenatal nicotine exposure by two different routes of drug administration, injection and infusion, on the development of monoaminergic systems and open field behavior in the neonatal and juvenile rat. The nicotine administration to pregnant Sprague-Dawley rats was carried out by subcutaneous injection (3 mg/kg twice daily) or infusion via implanted osmotic minipumps (6 mg/kg/day) from gestational day 4 (GD4) until GD20. At postnatal day 7 (PD7), 15 and 22, the contents of the neurotransmitters and their metabolites including noradrenaline (NA), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), homovanilic acid (HVA), serotonin (5-HT) and 5-hydroxy-3-indolacetic acid (5-HIAA) were measured in the midbrain+pons - medulla (M + P - M), forebrain and cerebellum. Prenatal nicotine exposure caused a persistent reduction of DA turnover in the forebrain at PD15 and PD22. In addition, the 5-HT system was also affected by prenatal nicotine, and reductions of 5-HT turnover in the M + P - M at PD15 and in the forebrain and the cerebellum at PD22 were found. Although there was no effect of prenatal nicotine on NE contents, the involvement of this system remains uncertain since we measured only NE contents without metabolites. In the present study, we also found significant route-related changes in the contents of the monoamines and metabolites in the NA, DA and 5-HT systems in all brain regions in rat offspring besides the effects of prenatal nicotine. In addition, the difference in administration route reflected the results of the open field test and the number of ambulations in the injection-group was less than that in the infusion-groups with no relation to nicotine administration. Therefore, such effects of "prenatal stress" accompanied by drug administration are not negligible in considering the risk assessment of prenatal nicotine exposure.

Analysis of Variance↗
PubMed1997

Prenatal dexamethasone exposure alters brain monoamine metabolism and adrenocortical response in rat offspring.

In this study, it has been clearly demonstrated that prenatal dexamethasone treatment (Dex; 0.05 mg/kg on gestational days 17, 18, and 19) resulted in the significant reductions of 5-hydroxytryptamine (5-HT) turnover in four brain regions, including the neocortex, hippocampus, hypothalamus, and midbrain + pons-medulla (M + P-M) but not in the striatum in the offspring at 3 and 14 wk of life, as well as dopamine turnover in the hypothalamus. [3H]paroxetine binding densities were increased in the hypothalamus and M + P-M at 14 wk of life, which corresponded to increased 5-HT contents in both regions. On the other hand, significantly lower norepinephrine contents in the neocortex and hippocampus were observed in the Dex group compared with the control group at 14 wk of life. In addition, the exposure to new environmental condition elevated blood corticosterone levels and enhanced behavioral activities to a greater extent in the Dex group than in controls at 7 wk of life, suggesting that elevated glucocorticoid levels during the pregnancy mimicked prenatal mild stress, producing developmental alterations in brain monoamine metabolism, endocrine response, and behavior in adult offspring.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1996

FGF-2 influences cell movements and gene expression during limb development.

FGF-2 is proposed to be an important ectodermal signal directing limb outgrowth and patterning. Consistent with this hypothesis we show that ectopic application of FGF-2 can maintain the apical ectodermal ridge (AER)-dependent expression of Sonic hedgehog (Shh), and AER-dependent zone of polarizing activity (ZPA) signaling. We also find that ectopic FGF-2 applied to the posterior wing bud caused a dramatic change in the morphology of the limb bud, and results in limbs that display a reduction in the length of individual skeletal elements and loss of digits. Associated with these morphological changes was an FGF-2-stimulated expansion and bifurcation of the expression domains of two posteriorly expressed genes, Shh and HoxD13. Applying FGF-2 at a central or anterior location in the limb bud did not alter the Shh expression domain or cause digit loss. To test whether ectopic application of FGF-2 into the posterior limb bud was influencing the movement of limb bud cells, we used the lipophilic dye DiI to map the behavior of posterior cells in response to FGF-2. In response to FGF-2 posterior limb bud cells move in both a proximal and a distal direction, causing the initially labeled cell population to bifurcate into two distinct domains. Our data suggest that FGF-2 is influencing limb outgrowth by modifying cell movements and subsequent position-specific cell-cell interactions that are important for limb morphogenesis.

Animals↗
PubMed1995

Increased 5-HT2 receptor-mediated behavior 11 days after shock in learned helplessness rats.

In the learned helplessness procedure, rats can be differentiated into two distinct groups. Learned helplessness (LH) rats do not learn to escape a controllable shock while non-learned helplessness (NLH) rats learn this response. This deficit in performance in LH rats lasted for 11 days. In LH rats, pretreatment with acute desipramine (15 mg/kg i.p.) or chronic diazepam (0.95 mg/kg/day p.o. for 7 days) did not produce recovery from this deficit of performance, but pretreatment with chronic desipramine (17.7 mg/kg/day p.o. for 7 days) or chronic mianserin (6.1 mg/kg/day p.o. for 7 days) led to recovery. Before presentation of uncontrollable shock, there was no difference between LH and NLH rats, but 11 days after the shock, head shakes induced by (+/-)-1-(2,5-demethoxy-4-iodophenyl)-2-aminopropane (DOI) in LH rats was significantly more frequent than those in NLH and naive rats without change of [3H]ketanserin binding. The basal corticosterone level was higher in LH rats than in NLH rats. These findings suggest that the learned helplessness model is a reliable animal model of depression accompanied by 5-HT2 receptor hypersensitivity.

Animals↗
PubMed1995

Digit tip regeneration correlates with regions of Msx1 (Hox 7) expression in fetal and newborn mice.

We report that during mouse fetal development transcripts of Msx1 and Msx2 become progressively restricted to cells that will form more distal digit structures; the Msx2 expression domain is always more distal than Msx1. At birth both Msx1 and Msx2 are expressed in cells of the nail bed and hair follicle. We have found that the regenerative ability of mouse digit tips is restricted to levels in which the amputation plane is within the region of Msx1, but not Msx2, expression in early fetal digits and to levels where both Msx1 and Msx2 are expressed in late fetal and neonatal digits. Fetal digit tip regeneration is rapid and completed by birth, whereas neonatal digit tip regeneration requires 4 weeks and is sometimes imperfect. In both fetal and neonatal digits, we find that both Msx1 and Msx2 are expressed during regeneration, but not during wound healing associated with proximal amputations where no regenerative response is observed. These data support the hypothesis that the expression of Msx genes are important for digit cells to initiate and participate in a regenerative response.

Animals↗
PubMed1994

Periodic maternal deprivation-induced potentiation of the negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response persists throughout the animal's life-span.

In this study, it was clearly demonstrated that the enhanced negative feedback sensitivity to glucocorticoids to inhibit stress-induced adrenocortical response, which was produced by periodic maternal deprivation (PMD) treatment for the first 3 weeks of life, did persist in rats tested at 66 and 92 weeks of life, suggesting that some stressful experience during early life permanently alters the adrenocortical response to stressful stimuli. This effect of PMD was not accompanied by an increased density of glucocorticoid receptor binding sites in the hippocampus from 93-week-old rats.

Adrenal Cortex↗
PubMed1994

Regeneration of HoxD expression domains during pattern regulation in chick wing buds.

The expression domains of genes located at the 5' end of the HoxD (formerly Hox-4) complex appear to correlate with pattern along both the proximal-distal (PrDi) and the anterior-posterior (AP) axes of the developing limb bud, and it has been suggested that the HoxD gene products are involved in the specification of positional information during limb development. The apical ectodermal ridge is required for limb outgrowth and is thought to influence mesodermal cells at the distal end of the limb bud in a region within which patterning events occur. In this paper, we examine the expression of 5' HoxD genes during PrDi pattern regulation in chick wing buds. In limbs undergoing pattern regulation, we demonstrate that the domains of HoxD11 and HoxD13 gene expression are "regenerated" within 24 hr of removal of the distal mesenchyme. In contrast, in limbs which will not form distal structures, HoxD13 expression becomes reduced.

Animals↗
PubMed1994

FGF-2 induces regeneration of the chick limb bud.

The chick limb bud is unable to mount a regenerative response following amputation at any stage of its development. Local application of heparan sulfate conjugated beads loaded with fibroblast growth factor-2 (FGF-2) onto an amputated stage 25 chick limb bud results in a high frequency (88%) of limbs in which the regeneration of digit-like structures was induced. The regenerative response is associated with the location of the FGF-2-loaded beads on the limb stump. This is the first report of the induction of a regenerative response in a higher vertebrate limb by a chemically defined agent.

Animals↗
PubMed1994

Conversion of anterior limb bud cells to ZPA signaling cells in vitro and in vivo.

Following a graft of posterior (zone of polarizing activity or ZPA) cells into the anterior margin of the developing chick wing bud, anterior cells are induced to alter their developmental fate and form structures that are normally composed of posterior cells. When anterior cells are cultured under microdissociation conditions they develop ZPA signaling ability within 24 hr. ZPA signaling in these cultures is transient and once established the level of ZPA signaling declines with time in culture. ZPA signaling in anterior cells is sensitive to treatment with fibroblast growth factor-2 (FGF-2); the development of ZPA signaling is inhibited when nonsignaling anterior cells are cultured in the presence of FGF-2. Conversely, when anterior cells that have developed ZPA signaling are treated with FGF-2, ZPA signaling levels are maintained. Thus, our results suggest that FGF-2 maintains or stabilizes the positional character of anterior (nonsignaling) cells, as well as anterior ZPA signaling converted cells, and posterior (ZPA signaling) limb bud cells in vitro (R. Anderson, M. Landry, and K. Muneoka (1993) Development 117, 1421-1433). In addition, anterior cells will convert to ZPA signaling cells in vivo following apical ectodermal ridge (AER) removal, suggesting that a factor(s) localized to the AER prevents anterior cells from developing ZPA signaling capability during limb outgrowth. These findings indicate that nonsignaling anterior limb bud cells have the potential to become ZPA signaling cells and that FGF-2, or a related factor, functions in the maintenance of positional states in the developing limb.

Animals↗