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PubMed1997

Structural and mechanistic bases for the induction of mitotic chromosomal loss and duplication ('malsegregation') in the yeast Saccharomyces cerevisiae: relevance to human carcinogenesis and developmental toxicology.

MultiCASE has the ability to automatically determine the structural features responsible for the biological activity of chemicals. In the present study, 93 chemicals tested for their ability to induce chromosomal 'malsegregation' in the yeast Saccharomyces cerevisiae were analyzed. This 'malsegregation' mimics molecular events that occur during human development and carcinogenesis resulting in an effective loss of one chromosome of an autosomal pair and duplication of the homologue. Structural features associated with the ability to induce such chromosome loss and duplication were identified and compared with those obtained from examination of other toxicological data bases. The most significant structural similarities were identified between the induction of chromosomal malsegregation and several toxicological phenomena such as cellular toxicity, induction of sister chromatid exchanges in vitro and rodent developmental toxicity. Very significant structural similarities were also found with systemic toxicity, induction of micronuclei in vivo and human developmental toxicity. Less significant structural overlaps were found between yeast malsegregation and rodent carcinogenicity, DNA reactivity and mutagenicity, and the induction of chromosome aberrations in vitro and sister chromatid exchanges in vivo. These overlaps may indicate mechanistic similarities between the induction of chromosomal malsegregation and other toxicological phenomena. The predictivity of the SAR model derived from the present data base is relatively low, however. This may be merely a reflection of the small size and composition of the data base, however, further analyses suggest that it reflects primarily the multiple mechanisms responsible for the induction of chromosomal malsegregation in yeast and the complexity of the phenomenon.

Carcinogens↗
PubMed2003

An increased expression of the mGlu5 receptor protein following LTP induction at the perforant path-dentate gyrus synapse in freely moving rats.

The involvement of metabotropic glutamate (mGlu) receptors in the induction of long-term potentiation (LTP) in vivo has been consistently documented. We have investigated whether LTP induction in the dentate gyrus of rats leads to changes in expression of mGlu2/3 or -5 receptor subtypes in the hippocampus. LTP was induced at the medial perforant path-dentate gyrus synapses, and mGlu receptor expression was examined by Western blot or in situ hybridization. An up-regulation of mGlu5 receptors was observed in the hippocampus both 24 and 48 h following LTP induction. This effect was restricted to the dentate gyrus and CA1 region, whereas no changes in mGlu5 receptor protein (but an increase in mRNA levels) were observed in the CA3 region. The increased expression of mGlu5 receptors was directly related to the induction of LTP, because it was not observed when tetanic stimulation was carried out in animals treated with the NMDA receptor antagonist, 2-amino-5-phosphonopentanoate (AP5). Western blot analysis also showed a reduced expression of mGlu2/3 receptors in the whole hippocampus 24 h after LTP induction, indicating that the increased expression of mGlu5 receptors was specific. These data suggest that an up-regulation of mGlu5 receptors is a component of the plastic changes that follow the induction of LTP at the perforant path-dentate gyrus synapse.

2-Amino-5-phosphonovalerate↗
PubMed2003

Impact of labor induction, gestational age, and maternal age on cesarean delivery rates.

OBJECTIVE: To quantify the impact of labor induction and maternal age on cesarean delivery rates in nulliparous and multiparous women between 36 and 42 weeks' gestation. METHODS: We performed a retrospective cohort study on 14,409 women delivering at two teaching hospitals in metropolitan Boston during 1998 and 1999. Women who had contraindications to labor, including a prior cesarean delivery, were excluded. The risks for cesarean delivery by induction status, gestational age by completed week between 36 and 42 weeks, maternal age <35, 35-39, and >/=40 years, and stratified by parity, were calculated by logistic regression. RESULTS: In nulliparas, labor induction was associated with an increase in cesarean delivery from 13.7% to 24.7% (adjusted odds ratio [OR] 1.70; 95% confidence interval [CI] 1.48, 1.95]). In multiparas, induction was associated with an increase from 2.4% to 4.5% (OR 1.49; 95% CI 1.10, 2.00). Other variables that placed a nulliparous woman at increased risk for cesarean delivery included maternal age of at least 35 years and gestational ages over 40 weeks. For multiparas, only maternal age 40 years or older and gestational age of 41 weeks were associated with an increase in cesarean deliveries. CONCLUSION: Induction of labor, older maternal age, and gestational age over 40 weeks each independently increase the risk for cesarean delivery in both nulliparous and multiparous women. Although the relative risk from induction is similar in nulliparas and multiparas, the absolute magnitude of the increase is much greater in nulliparas (11% versus 2.1%).

Adult↗
PubMed1997

A randomized trial of misoprostol and oxytocin for induction of labor: safety and efficacy.

OBJECTIVE: To compare the safety and efficacy of misoprostol and oxytocin for induction of labor. METHODS: One hundred thirty women requiring induction of labor were randomized to receive either intravenous oxytocin or 100 micrograms misoprostol, administered intravaginally every 4 hours until labor was established. RESULTS: Compared with women receiving oxytocin, a greater percentage of women in the misoprostol group had Bishop scores of 3 or less (58 versus 38%, P < .05). Nonetheless, the median induction-to-delivery interval was significantly shorter (585 versus 885 minutes, P < .001) in the misoprostol group. Women in the misoprostol group were more likely to deliver vaginally within 24 hours of the start of induction (77 versus 55%, P < .002). Epidural analgesia was used more frequently in women receiving oxytocin than in those receiving misoprostol (73 versus 50%, P = .025). The total percentage of cesarean deliveries was not significantly different, although the percentage of cesarean deliveries for dystocia was lower in the misoprostol group (8 versus 21%, P = .02). Uterine tachysystole was significantly more common (70 versus 11%, P < .001) and hospital charges significantly less with misoprostol. CONCLUSION: Compared with oxytocin for labor induction, misoprostol results in a shorter induction-to-delivery interval, a reduction in the rate of cesarean delivery for dystocia, and a decreased use of epidural analgesia. Uterine tachysystole is significantly more common with the use of misoprostol.

Adult↗
PubMed1998

A randomized trial of misoprostol and extra-amniotic saline infusion for cervical ripening and labor induction.

OBJECTIVE: To compare the cesarean rates in women undergoing induction of labor with unfavorable cervices who receive either misoprostol or extra-amniotic saline infusion. METHODS: We assigned 250 women undergoing indicated induction of labor randomly to misoprostol (50 microg every 4 hours for three doses with or without oxytocin) or extra-amniotic saline infusion and oxytocin. Each eligible subject had a singleton gestation, vertex presentation, intact membranes, cervical dilation no more than 2 cm, and effacement no more than 50%. RESULTS: Two hundred forty-eight women were studied after two exclusions; 120 were assigned to misoprostol, and 128 to extra-amniotic saline infusion. This sample size ensured an 80% chance of detecting an intergroup difference in cesarean rates of at least two-fold. The groups were similar in age, race, parity, indication for induction, and gestational age. The extra-amniotic saline infusion group had a significantly lower median initial dilation; however, at 12 hours, this group was significantly more dilated. The groups also were similar in epidural use, chorioamnionitis rates, endometritis rates, birth weights, and neonatal outcomes. Overall, 23% of women underwent cesarean deliveries, 18% and 27% for the misoprostol and extra-amniotic saline infusion groups, respectively (P = .12). There were no significant differences in the median time to either vaginal or cesarean delivery between the two groups. Eighty-one percent of women were delivered in less than 24 hours from initiation of induction; 78% in the misoprostol group, and 84% in the extra-amniotic saline infusion group (P = .19). CONCLUSION: Both methods of labor induction appear to be equally effective in this group of women at high risk for cesarean delivery and prolonged induction of labor.

Adult↗
PubMed1998

Maternal serum dehydroepiandrosterone sulfate levels and successful labor induction.

OBJECTIVE: To evaluate the maternal serum dehydroepiandrosterone (DHEA) sulfate level as a factor associated with the outcome of labor induction. METHODS: Venous blood was collected from 161 women at the initiation of labor induction. Pregnancies complicated by maternal corticosteroid use, antepartum chorioamnionitis, or cesarean delivery for indications other than arrest disorders were excluded from analysis. In 155 women meeting inclusion criteria, induction followed established protocols. Serum DHEA sulfate levels were measured by radioimmunoassay and correlated with the outcome of each induction attempt. A success was defined as progression to active labor. The Welch approximate t test, Mann-Whitney test, Fisher exact test, simple regression, and multiple regression were used for statistical analysis, with P < .05 considered significant. RESULTS: The mean (+/- standard error) DHEA sulfate level was higher in women who progressed to active labor (n = 147) than in those with unsuccessful attempts (n = 8), (109.01 +/- 5.19 microg/dL versus 58.78 +/- 15.83 microg/dL, respectively; P = .02). Compared with women with DHEA sulfate levels above 70 microg/dL, women with lower levels had an unsuccessful induction odds ratio (OR) of 4.46 (95% confidence interval, 1.12, 17.67; P = .04). The OR increased as DHEA sulfate levels decreased. CONCLUSION: Dehydroepiandrosterone sulfate may be an important factor in successful labor induction.

Adult↗
PubMed2001

Two competing mechanisms underlying neon color spreading, visual phantoms and grating induction.

Neon color spreading is closely related to the photopic visual phantom illusion, since these two completion phenomena are characterized by in-phase lightness induction, and the only difference in the stimulus configuration is the difference in the inducer height. This idea was supported by the present study. Neon color spreading showed almost the same function of critical spatial frequency as photopic visual phantoms (Experiment 1), and the critical spatial frequency was constant as the inducer height was changed (Experiment 2). We also examined the relationship between neon color spreading and grating induction (characterized by counterphase lightness induction) in critical spatial frequency (Experiment 3) and in magnitudes of lightness induction (Experiment 4) as a function of the inducer height. The inducer height at which in-phase (neon color spreading) appearance gave way to counterphase (grating) induction was approximately 0.1 deg. These results suggest that neon color spreading shares a common neural mechanism with the photopic visual phantom illusion and that this mechanism is different from, and competes with, the mechanism of grating induction.

Color Perception↗
PubMed1996

Micronucleus induction by chromium and selenium, and suppression by metallothionein inducer.

The clastogenic effects of chromium compounds (CrCl3 and K2CrO4) and selenium compounds (H2SeO3 and Na2SeO4) in mouse bone marrow cells have been investigated. K2CrO4 induced significant, dose-related increases in micronuclei. H2SeO3 also showed a significant micronucleus induction at the highest dose. CrCl3 and Na2SeO4 were negative for micronuclei induction in mice. The suppressive effect of Bi(NO3)3, a metallothionein inducer, on the micronucleus induction by K2CrO4 and H2SeO3 has been also investigated. Pretreatment with Bi(NO3)3 suppressed the micronucleus induction by K2CrO4 and H2SeO3. In addition, the incidence of micronucleus induction seemed to be reduced by double dosing with K2CrO4 and H2SeO3, compared to single dosing. It is generally recognized that a number of metal compounds induce metallothionein synthesis. These results suggest that the mechanism of suppression of micronucleus induction by K2CrO4 and H2SeO3 involve possible participation of metallothionein in mouse bone marrow.

Animals↗
PubMed2003

Differential metallothionein induction patterns in three freshwater fish during sublethal copper exposure.

We assessed whether fish that tolerate higher levels of Cu exposure have a higher capacity to induce metallothionein (MT) synthesis than other, more sensitive, fish species. Furthermore, we examined if a correlation could be found between tissue Cu accumulation and MT levels. Cu accumulation and MT concentrations in gill, liver, kidney and muscle of rainbow trout (Oncorhynchus mykiss), common carp (Cyprinus carpio) and gibel carp (Carassius auratus gibelio) were measured during a 1 week exposure to a sublethal Cu (1 microM). Different patterns were observed for the three species regarding Cu accumulation as well as MT induction. Virtually no Cu accumulation was seen in rainbow trout gill, while in both cyprinid species gill Cu levels increased three- to four-fold. Cu accumulated fast in common carp (within the first day), but slow in gibel carp (1 week). Gill MT induction was obvious in gibel carp only, with an increase of 156% after 1 week of exposure. Liver accumulated most Cu in rainbow trout (235% increase) and common carp (144% increase), with Cu levels in liver being significantly higher in rainbow trout compared to the carp species from the start. MT induction was pronounced in common carp liver only (138% increase). In gibel carp liver, there was no clear Cu accumulation or MT induction. In contrast, gibel carp was the only species to show Cu accumulation in kidney after 3 days of exposure (83% increase), after which levels returned to normal. Concomitantly, gibel carp kidney was also the only kidney tissue to show MT induction (192-195% increase after 3 and 7 days). In common carp, a significant decrease of kidney MT levels was observed from day 1 onwards. In muscle, Cu accumulation was clear for the two cyprinid species (three- to four-fold increase) but not for rainbow trout. Of the species studied, gibel carp is the most resistant to copper polluted environments, and showed a positive significant relationship between tissue copper concentrations and MT levels in gill, liver and muscle tissues. Common carp showed an intermediate response, with significant correlations in liver and muscle tissue. In contrast, we found low MT induction in rainbow trout, the most sensitive species, and no correlation at all between MT concentrations and tissue copper contents. Possibly, the regulatory capacity for copper homeostasis was exceeded in rainbow trout, and MT synthesis inhibited.

Animals↗
PubMed2000

Effects of pH on the induction of phosphoenolpyruvate carboxylase kinase in Kalanchoë fedtschenkoi.

Previous work has shown that an increase in cytosolic pH plays an important role in the induction of phosphoenolpyruvate carboxylase (PEPc) kinase by light in C(4) plants. The potential involvement of a similar effect in the induction of PEPc kinase in the Crassulacean acid metabolism (CAM) plant Kalanchoë fedtschenkoi was assessed using leaf disks. Treatment of disks with the weak base NH(4)Cl did not affect induction of the kinase. Prolonged treatment of disks with weak acids prevented both decarboxylation of malate during the day and induction of the kinase in the following night, but short treatments had no effect. The data are consistent with the view that a high cytosolic malate content can prevent induction of phosphoenolpyruvate carboxylase kinase. Changes in cytosolic pH may affect induction of the kinase in CAM plants by a secondary effect rather than as part of a primary signalling pathway.

Journal Article↗
PubMed1999

Anti-oxidants prevent focal rat brain injury as assessed by induction of heat shock proteins (HSP70, HO-1/HSP32, HSP47) following subarachnoid injections of lysed blood.

The initial aim of this study was to determine if the HSP70 (the main inducible heat shock protein), HO-1 (heme oxygenase-1, HSP32) and HSP47 (a collagen chaperone) stress proteins were induced in the same focal regions of rat brain following experimental subarachnoid hemorrhage (SAH). The next objective was to determine whether anti-oxidants prevented the stress gene expression in the focal regions. Lysed blood (150 microliter) was injected into the subarachnoid space of adult, female Sprague-Dawley rats via the cisterna magna. Animals were sacrificed 24 h later. Immunocytochemistry showed focal regions of stress gene induction in most animals (13/21), HSP70 and HO-1 proteins being expressed in neurons, microglia and astrocytes and HSP47 being expressed in microglia. Co-induction of the same three stress proteins was observed in focal areas in the striatum and cerebellum as well. In the 13 animals with focal regions of stress gene induction there were 8.1+/-1.8 foci in cortex, 5.5+/-0.9 foci in striatum, and 11.7+/-7.3 foci in cerebellum in the brain of each animal. The focal regions of stress gene induction varied in size from 200 micrometer to 7 mm in diameter. Systemic administration of the tirilazad-like anti-oxidants U101033E (n=8) and U74389G (n=7) completely blocked stress protein induction in focal brain regions normally produced by cisternal injections of lysed blood. There were fewer drug treated animals (0/15) with focal areas of stress gene induction compared to non-drug (13/21) treated animals following the cisternal lysed blood injections (p<0.01 using Fisher's probability test). This study shows that anti-oxidants prevent focal regions of injury as assessed by heat shock protein expression in a rat model of SAH.

Animals↗
PubMed1988

Dose-dependence of and threshold for optimal bone induction by collagenous bone matrix and osteogenin-enriched fraction.

Subcutaneous implantation of demineralized collagenous bone matrix results in local induction of new bone formation. The dose dependence of bone induction was investigated using different amounts of rat demineralized bone matrix (DBM) and also osteogenin-enriched fraction with and without inactive collagenous bone matrix (ICBM). There is a threshold for bone induction; at least 10 mg of DBM is required. There is a dose dependent increase in bone induction between 10 to 25 mg. Exogenous type I collagen was found to be stimulatory to bone induction when suboptimal doses of DBM are employed. The activity of osteogenin-enriched dissociative extract was enhanced by addition of ICBM. These results imply that optimal bone induction requires the combined action of soluble osteogenin-enriched fraction and insoluble collagenous substratum.

Alkaline Phosphatase↗
PubMed2002

Induction of PAH-catabolism in mushroom compost and its use in the biodegradation of soil-associated phenanthrene.

This paper describes the induction of phenanthrene-catabolism within Phase II mushroom compost resulting from its incubation with (1) phenanthrene, and (2) PAH-contaminated soil. Respirometers measuring mineralization of freshly added 14C-9-phenanthere were used to evaluate induction of phenanthrene-catabolism. Where pure phenanthrene (spiked at a concentration of 400 mg kg(-1) wet wt.) was used to induce phenanthrene-catabolism in compost, induction was measurable, with maximal mineralization observed after 7 weeks phenanthrene-compost contact time. Where PAH-contaminated soil was used to induce phenanthrene-catabolism in un-induced compost, induction was observed after 5 weeks soil-compost contact time. Microcosm-scale amelioration of soil contaminated with 14C-phenanthrene (aged in soil for 516 days prior to incubation with compost) indicated that both induced (using pure phenanthrene) and uninduced Phase II mushroom composts were equally able to promote degradation of this soil-associated contaminant. After 111 days incubation time, 42.7 +/- 6.3% loss of soil-associated phenanthrene was observed in the induced-compost soil mixture, while 36.7 +/- 2.9% loss of soil-associated phenanthrene was observed in the uninduced-compost soil mixture. These results are notable as they indicate that while pre-induction of phenanthrene-catabolism within compost is possible, it does not significantly increase the extent of degradation when the compost is used to ameliorate phenanthrene-contaminated soil. Thus, compost could be used directly in the amelioration of contaminated land i.e. without pre-induction of catabolism.

Agaricales↗
PubMedDate not supplied

DNA replication and indirect induction of the SOS response in Escherichia coli.

The SOS response can be induced indirectly in Escherichia coli by infection with UV irradiated bacteriophage P1, lambda or M13. Induction, monitored quantitatively by means of a sfiA::lac operon fusion, was stronger with the plasmid phage P1 than with lambda, but the kinetics were similar, showing that plasmid and non-plasmid phages are not fundamentally different in their ability to produce indirect induction. In the absence of lambda DNA replication the level of induction was strongly reduced, indicating that the attempt to replicate damaged DNA results in induction of the SOS response. The slight residual induction observed in the absence of DNA replication suggests the existence of a second pathway leading from DNA lesions to induction of the SOS response.

Coliphages↗
PubMed2000

Inactivation of alpha7 ACh receptors and activation of non-alpha7 ACh receptors both contribute to long term potentiation induction in the hippocampal CA1 region.

Acute and chronic nicotine exposure differentially facilitate the induction of long-term potentiation (LTP), a synaptic model of learning and memory, in the hippocampal CA1 region. The mechanisms underlying these effects of nicotine, however, are unknown. In the present study, both nicotinic acetylcholine receptor (nAChR) agonists and an alpha7 nAChR antagonist facilitated the induction LTP in the hippocampal CA1 region of naive rat. Furthermore, chronic nicotine treatment lowered the threshold for induction of LTP, and acute application of nicotinic agonists, but not an alpha7 antagonist, further facilitated LTP induction in the chronic-nicotine-treated hippocampus. These results suggest not only that both activation of non-alpha7 nAChRs and inactivation of alpha7 nAChRs contribute to LTP induction, but also that chronic-nicotine-mediated facilitation of LTP induction is due to chronic-nicotine-induced desensitization of alpha7 nAChRs.

Animals↗
PubMed1999

Generation of reactive oxygen intermediates, activation of NF-kappaB, and induction of apoptosis in human endothelial cells by glucose: role of nitric oxide synthase?

Exposure to high glucose causes characteristic dysfunction and morphologic changes of the endothelium. To study the underlying mechanisms of glucotoxicity, human endothelial cells (HUVECs) were isolated from umbilical veins and cultivated under hyperglycemic conditions (10-30 mM) for up to 72 h. The generation of reactive oxygen intermediates (ROIs) was determined by histochemical staining of the cells by dichlorodihydrofluorescein. Activation of the transcription factor nuclear factor-kappa B (NF-KB) family was analyzed by the electromobility shift assay and by histochemical staining of the cells with rhodamine-labelled consensus sequences of activated NF-KB. Apoptotic cells were identified by morphologic analysis and DNA fragmentation. Incubation of HUVECs with high glucose led to rapid increase in the generation of ROIs. After an incubation of 2 to 6 h, NF-KB became activated, with the maximum at 4 h. Exposure of HUVECs to high glucose for up to 72 h caused a significant induction of apoptosis in HUVECs. The increased generation of ROIs, activation of apoptosis, and induction of apoptosis were also observed in cells incubated with 3-O-methyl-D-glucose, a glucose derivative that is taken up by the cells but not metabolized. Generation of ROIs, activation of NF-kappaB, and induction of apoptosis were not only prevented by antioxidants (thioctic acid, tocopherol, superoxide dysmutase-mimetic), but also by L-nitroarginine. These observations indicate that high glucose leads to an increase in generation of ROIs, an activation of NF-KB, and an induction of apoptosis by a glucose-specific and NO synthase-dependent mechanism. Our data suggest that peroxynitrite, which is rapidly formed from nitric oxide and superoxide anions, is the mediator of the cytotoxic effects of high glucose on endothelial cells. Because the induction of apoptosis by glucose was prevented by an antisense nucleotide to the p65NF-kappaB binding site, we assume that the ROI-mediated activation of NF-kappaB plays an important role for induction of apoptosis by glucose.

3-O-Methylglucose↗
PubMed2001

Survival and induction of SOS in Escherichia coli treated with cisplatin, UV-irradiation, or mitomycin C are dependent on the function of the RecBC and RecFOR pathways of homologous recombination.

Resistance of tumors to drugs such as cisplatin and mitomycin C (MMC) is an important factor limiting their usefulness in cancer chemotherapy. The antitumor effects of these drugs are due to the formation of bifunctional adducts in DNA, with cisplatin causing predominantly intrastrand-crosslinks and MMC causing interstrand-crosslinks. The SOS chromotest was used to study the cellular mechanisms that process DNA damage in Escherichia coli exposed to cisplatin, ultraviolet irradiation (UV) and MMC and subsequently facilitate the production of a molecular signal for induction of the SOS response. Strains used in the SOS chromotest have a fusion of lacZ with the sfiA (sulA) gene so that the amount of SOS inducing signal, which is modulated by the ability of the cell to repair DNA, is measured by assaying beta-galactosidase activity. SOS induction in a strain proficient in homologous recombination (HR) was compared with that in isogenic strains deficient in HR due to a blocked RecBC pathway caused by a recB mutation or a blocked RecFOR pathway caused by a recO mutation. The effect of cisplatin treatment in a uvrA mutant strain blocked at the first step of NER was compared with that in an isogenic strain proficient in NER. Cellular resistance was measured as percent colony forming units (cfu) for cells treated with increasing doses of cisplatin, MMC and UV relative to that in untreated control cultures. The importance of both HR pathways for resistance to these treatments was demonstrated by decreased survival in mutants with the recB mutant being more sensitive than the recO mutant. SOS induction levels were elevated in the sensitive recB strain relative to the HR proficient strain possibly due to stalled and/or distorted replication forks at crosslinks in DNA. In contrast, induction of SOS was dependent on RecFOR activity that is thought to act at daughter strand gaps in newly synthesized DNA to mediate production of the signal for SOS induction. Proficiency in NER was necessary for both survival and high levels of SOS induction in cisplatin treated cells.

Bacterial Proteins↗
PubMed2002

Fgf8 and Fgf3 are required for zebrafish ear placode induction, maintenance and inner ear patterning.

The vertebrate inner ear develops from initially 'simple' ectodermal placode and vesicle stages into the complex three-dimensional structure which is necessary for the senses of hearing and equilibrium. Although the main morphological events in vertebrate inner ear development are known, the genetic mechanisms controlling them are scarcely understood. Previous studies have suggested that the otic placode is induced by signals from the chordamesoderm and the hindbrain, notably by fibroblast growth factors (Fgfs) and Wnt proteins. Here we study the role of Fgf8 as a bona-fide hindbrain-derived signal that acts in conjunction with Fgf3 during placode induction, maintenance and otic vesicle patterning. Acerebellar (ace) is a mutant in the fgf8 gene that results in a non-functional Fgf8 product. Homozygous mutants for acerebellar (ace) have smaller ears that typically have only one otolith, abnormal semi-circular canals, and behavioral defects. Using gene expression markers for the otic placode, we find that ace/fgf8 and Fgf-signaling are required for normal otic placode formation and maintenance. Conversely, misexpression of fgf8 or Fgf8-coated beads implanted into the vicinity of the otic placode can increase ear size and marker gene expression, although competence to respond to the induction appears restricted. Cell transplantation experiments and expression analysis suggest that Fgf8 is required in the hindbrain in the rhombomere 4-6 area to restore normal placode development in ace mutants, in close neighbourhood to the forming placode, but not in mesodermal tissues. Fgf3 and Fgf8 are expressed in hindbrain rhombomere 4 during the stages that are critical for placode induction. Joint inactivation of Fgf3 and Fgf8 by mutation or antisense-morpholino injection causes failure of placode formation and results in ear-less embryos, mimicking the phenotype we observe after pharmacological inhibition of Fgf-signaling. Fgf8 and Fgf3 together therefore act during induction and differentiation of the ear placode. In addition to the early requirement for Fgf signaling, the abnormal differentiation of inner ear structures and mechanosensory hair cells in ace mutants, pharmacological inhibition of Fgf signaling, and the expression of fgf8 and fgf3 in the otic vesicle demonstrate independent Fgf function(s) during later development of the otic vesicle and lateral line organ. We furthermore addressed a potential role of endomesomerm by studying mzoep mutant embryos that are depleted of head endomesodermal tissue, including chordamesoderm, due to a lack of Nodal-pathway signaling. In these embryos, early placode induction proceeds largely normally, but the ear placode extends abnormally to midline levels at later stages, suggesting a role for the midline in restricting placode development to dorsolateral levels. We suggest a model of zebrafish inner ear development with several discrete steps that utilize sequential Fgf signals during otic placode induction and vesicle patterning.

Acridine Orange↗