Biomedical subjects

T Jaskoll

Publications and source records attributed to T Jaskoll.

36 records · Page 2Linked to original sources

PubMed1993

H-2 gene complex and corticosteroid responsiveness: evidence that the corticosteroid hormone signal transduction pathway in the adult mouse lung is not associated with haplotype-specific responses to corticosteroids.

Differential responsiveness to corticosteroids (CORT) has been shown to be related to HLA haplotype. A strong association between the mouse homolog to the human HLA complex, the H-2 complex, and intrauterine responses to CORT have also been demonstrated; haplotype differences alter CORT-induced susceptibility to cleft palate and temporal differences in lung maturation. Since variation in the glucocorticoid receptor (GR) is associated with tissue specific responses to CORT, we hypothesize that haplotype-specific CORT responsiveness may be regulated by H-2 associated modification of GR expression and/or function. Given that H-2 congenic mice are genetically identical except at the H-2 complex on mouse chromosome 17 and the GR structural gene is encoded on chromosome 18, the GR gene is identical in these mice. However, any step in the GR signal transduction pathway may be regulated by gene(s) at or near the H-2 complex and result in haplotype-specific differences in CORT responsiveness. We have investigated differences in qualitative and quantitative characteristics of the adult B10 (H-2b) and B10.A (H-2a) pulmonary GR by Scatchard analysis, immunochemical and biochemical assays. No differences in the GR binding parameters (BMAX and Kd), receptor form and level, or ligand-GR complex binding to glucocorticoid response element (GR-GRE) were detected, leading us to conclude that H-2 associated factors do not regulate the relative intrauterine responses to CORT by modulating the adult GR.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗

PubMed1991

Neural tube and neural crest: a new view with time-lapse high-definition photomicroscopy.

The dynamic process of neural tube formation and neural crest migration in live, unstained cultured avian embryos at Hamburger-Hamilton (H.H.) stages 8-11 was investigated by time-lapse cinematography using a high-definition microscope. These studies have demonstrated that neural tube closure in the trunk region differs from that observed in the head. The cephalic neural folds elevate slowly, then make contact rapidly. Following this initial apposition, they gradually "zip-up" in the rostrad and caudad direction. In the trunk region where the neuroepithelium bulges adjacent to the somites, the edges of the folds pulsate and forcefully touch-retract-touch in these bulging regions; the intersomitic epithelia retract, remain open even after more posterior somitic regions have apposed, and then close slowly. Epithelial blebs and N-CAM antibody were observed at the leading edges of the neuroepithelia. Between the open folds only a few bridging cells were seen; they probably represent the sites of initial cell adhesion following epithelial retraction. Focusing into the developing embryo shows that neuroepithelial fusion occurs prior to surface epithelial fusion. A meshwork of synchronously pulsating neural crest cells was identified below the surface epithelium and a preliminary investigation of their initial migration was conducted.

Animals↗

PubMed1991

Mouse major histocompatibility complex and lung development: haplotype variation, H-2 immunolocalization, and progressive maturation.

The association of the mouse major histocompatibility complex (H-2), lung maturation, and corticosteroid responsiveness has recently been demonstrated in congenic B10 (H-2b) and B10.A (H-2a) mice (Hu et al.: American Journal of Medical Genetics 35:126-131, 1990). We have investigated additional haplotypes [B10.BR (H-2k) and B10.D2 (H-2d)] to confirm that there is a strong association between H-2 haplotype variation and the degree of pulmonary maturation. Lungs of B10.D2, B10.BR, B10, and B10.A congenic mice achieve haplotypic specific maturation: B10.D2 lungs greater than B10 lungs = B10.BR lung greater than B10.A lungs. It appears that the expression of these developmental potentials is under corticosteroid regulation. Further, to test the hypothesis that H-2 antigens would be expressed earlier in embryonic lungs with the H-2b (B10) or H-2k (B10.BR) haplotype than with the H-2a (B10.A) haplotype, we investigated the spatiotemporal patterns of H-2 antigen localization in B10, B10.BR, and B10.A congenic mouse strains with and without corticosteroid treatment. The spatial patterns of H-2 antigen localization was similar in the B10, B10.BR, and B10.A mouse lungs; however, these patterns appeared earlier in both untreated and treated B10 and B10.BR mice as compared with untreated B10.A mice, suggesting an H-2 haplotype associated rate of pulmonary maturation. Following corticosteroid treatment, all congenic strains had a temporally comparable spatial distribution of H-2 antigens. Our results provide preliminary evidence suggesting that both a lung "developmental gene(s)" and a "glucocorticoid responsiveness gene(s)" are most likely outside the K-D subregions of the H-2 complex. A model of the H-2 regulation of lung maturation and corticosteroid responsiveness is discussed.

Animals↗

PubMed1988

Corticosteroid-induced cleft palate in short-ear mice.

Corticosteroid-induced facial clefting was examined in short-ear mice (inbred strain SEA/GnJ from Jackson Laboratory). They were found to be gentle, prolific breeders (average litter size 7.3 +/- 2.6), with no increased fetal loss due to treatment. Although they have the most "resistant" H-2 haplotype (H-2d), they were found to be highly susceptible to corticosteroid-induced clefting, demonstrating that loci other than H-2 are involved in susceptibility. The short-ear locus itself is a plausible candidate, given that this gene on chromosome 9 leads to defective mesenchymal condensation, which in turn may render these mice extremely sensitive to teratogen exposure. Another gene or genes on chromosome 9 are also possibilities.

Animals↗

PubMed1984

Localization of H-2Kk in developing mouse teeth using monoclonal antibody.

The in situ distribution of H-2 antigens during mouse tooth morphogenesis was investigated using monoclonal antibodies to H-2Kk and indirect immunofluorescent techniques. H-2 antigens were detected in the basement membrane region of fetal molars; they were absent from both the epithelial and dental mesenchyme. H-2 antigens were not found in newborn and 4-day-old mouse molars.

Animals↗

PubMed1983

Corticosteroid-induced abnormality in fetal mice and H-2 haplotype: evidence of a cytoplasmic effect.

Different strains of H-2 congenic mice have different susceptibilities to corticosteroid-induced fetal loss and cleft palate. Applying this knowledge, we tested the null hypothesis, which assumes that there are no statistically significant differences in the frequency of abnormality among various types of treated backcross offspring and, thus, no evidence of a cytoplasmic effect. In the present study this null hypothesis was frequently, but not consistently, rejected. Therefore, there was some evidence of a cytoplasmic effect. One possible explanation of these results is seen when one considers the phenotypic effects of "gene-gene interaction" between variant H-2 genotypes and an invariant mitochondrial genotype.

Abnormalities, Drug-Induced↗

PubMed1983

H-2 haplotype and the embryotoxicity of serum from nonpregnant congenic mice.

Previous studies revealed a significant association between genes at or near the H-2 complex and fetal loss. Reasoning that the maternal serum might contain one or more unknown factors that are harmful to early embryonic or fetal development, or both, we performed an embryotoxicity screen using chick embryos and serum from nonpregnant C57BL/10Sn (H-2b) and B10.A/SnSg (H-2a) congenic mice. Serum from the strain with the higher frequency of fetal loss (C57BL/10 Sn) yielded a significantly greater frequency of chick abnormality, specifically neural tube malformation and death, than the serum from the strain with the lower frequency of fetal loss (B10.A/SnSg). Further, the C57BL/10 Sn serum demonstrated a highly significant dose-response. These results suggest that analogous studies may be profitable with women who have a history of chronic fetal wastage and/or offspring with neural tube defects.

Animals↗

PubMed1982

The effects of long-term fetal constraint in vitro on the cranial base and other skeletal components.

Recently it was suggested that some cases of premature closure of the sagittal suture in humans may be due to fetal head constraint. Using various modifications of the procedure for long-term shell-less cultivation of chick embryos, we sought to test the hypothesis that fetal head constraint may result in abnormalities of the cranial base and other skeletal structures of the head. Our experiments with various sized containers demonstrate that fetal constraint is associated with both deformation and malformation of the craniofacial skeleton, including the cranial base, squamosal, columella (stapes), and mandible. The severity of both deformation and malformation appears to be a function of the degree of fetal constraint. If, as some suggest, abnormality of the cranial base is the primary anomaly in craniosynostosis, then our results tend to support the fetal constraint hypothesis as one explanation of simple craniostenosis.

Animals↗

PubMed1982

Localization of H-2Kk in developing mouse palates using monoclonal antibody.

Using monoclonal antibodies to H-2Kk antigen, we sought to develop a reproduceable method of in situ localization in embryonic tissue and to determine whether there are specific patterns of H-2 localization in time and space in the developing palatal tissues of B10.A(H-2a) embryonic mice, with and without corticosteroid pretreatment at 12 days gestation. Our procedure employs ethanol-glacial acetic acid fixation, paraplast embedding, and enzymatic predigestion with purified hyaluronidase and neuraminidase. H-2 antigens were detected in palatal mesenchyme as well as basement membranes but not in oral or nasal epithelium. The pattern of distribution in mesenchyme of untreated embryos changed with progressive shelf development vertical leads to horizontal leads to epithelial fusion leads to epithelial seam degeneration leads to mesenchymal confluence. Although the palatal shelves of treated embryos remained vertical, corticosteroid treatment does not appear to alter the detectable spatiotemporal distribution of H-2 antigens in developing palates of embryonic B10.A mice.

Animals↗

PubMed1981

Corticosteroid-induced cleft lip in mice: a teratologic, topographic, and histologic investigation.

Unlike cleft palate, relatively few teratogens have been found to induce cleft lip in mice. The present study was designed to assess the teratologic, topographic (SEM), and histologic effects on lip morphogenesis following the administration of triamcinolone hexacetonide on the eighth day of gestation. The frequency of cleft lip in treated A/J mice was found to be more than three times greater than the spontaneous frequency in untreated controls. Comparable studies with other murine strains suggest no association between the cleft lip response and either a maternal effect or the H-2 complex. Affected A/J embryos showed a severe reduction in the size of the lateral nasal processes; affected embryos also demonstrated localized cell type-specific alterations, particularly in the epithelia and at the interface between epithelium and mesenchyme.

Abnormalities, Drug-Induced↗

PubMed1981

The association of H-2 haplotype with implantation, survival, and growth of murine embryos.

Using three congenic strains, C57BL/10Sn(H-2b), B10.A/SnSg(H-2a), and B10.D2/nSn(H-2d), we sought to investigate the possible association of H-2 haplotype with the number of implants, fetal survival, and fetal weight, as well as to analyze the possible effects of hybrid vigor and maternal-fetal histoincompatibility in primigravidae mice. The results of this study indicate a significant association between genes at or near the H-2 complex and both fetal loss and fetal weight, but not the number of implants. Haplotype variation accounted for 14 percent of the variation in fetal loss and 20 percent of the variation in fetal weight. With the exception of fetal loss, there was no evidence of a maternal effect. There was also no clear evidence of hybrid vigor or histoincompatibility effects for any of the three variables studied. In summary, the data suggests that particular allelic variants at or near the H-2 complex confer some selective advantage as measured by differential fetal survival and fetal growth.

Animals↗

PubMed1981

Corticosteroid-induced cleft palate in mice and H-2 haplotype: maternal and embryonic effects.

This report confirms and expands on the original preliminary observations made by Bonner and Slavkin that corticosteroid-induced cleft palate in mice is associated with H-2 haplotype. Using three congenic strains, B10, B10.A, and B10.D2, our studies demonstrate that B10.A (H-2a) is most susceptible and B10.D2(H-2d) is least susceptible, B10(H-2b) being intermediate. Variation in fetal loss among strains accounts for less than 1 percent of the variation in cleft-palate frequency among strains; variation in H-2 haplotype, however, accounts for more than 60 percent of the variation in cleft-palate frequency. With regard to all possible reciprocal F1 hybrids, our results indicate that while there is a significant maternal effect, maternal haplotype can account for only 11 percent of the variation in cleft-palate frequency among crosses. Embryonic haplotype accounts for 17 percent of the variation, which is indicative of an important embryonic effect. Finally, our studies suggest that susceptibility to corticosteroid-induced cleft palate is associated with the K end of the H-2 complex.

Adrenal Cortex Hormones↗

PubMed1981

Spatiotemporal patterns of fibronectin distribution during embryonic development. I. Chick limbs.

It has been suggested that an extracellular matrix - and cell surface - associated glycoprotein, fibronectin, plays a role in the positioning of cells in morphogenesis and in the maintenance of orderly tissue organization. In the present study the appearance and distribution of fibronectin during in ovo chick limb development has been investigated by indirect immunofluorescence techniques in H.H. stages 20-30. Fibronectin is not detectable until just prior to the transition from the morphogenetic to the cytodifferentiation phase of development. Beginning at H.H. stage 25, successive nonrandom patterns of fibronectin detection and distribution, which resemble the subsequent cartilaginous elements, precede overt chondrogenesis as detected by Alcian blue staining. This corresponds to the onset of the cytodifferentiation phase of limb development. As the accumulation of acidic proteoglycan increases in the cartilage matrix and the mesenchymal cells become more round in appearance, the presence of detectable fibronectin decreases and is ultimately seen only in the perichondria and basement membrane. However, predigestion of developed cartilage tissue with testicular hyaluronidase, prior to fibronectin staining, indicated that fibronectin remains a major constituent of cartilage matrix and is apparently masked by cartilage-specific proteoglycans. This study of chick limb development is consistent with the hypothesis that fibronectin may be a molecule that facilitates the spatial organization of cartilaginous primordia cytodifferentiation.

Animals↗

PubMed1981

Spatiotemporal patterns of fibronectin distribution during embryonic development. II. Chick branchial arches.

It has recently been demonstrated with the chick limb in ovo that successive nonrandom patterns of fluorescent staining with specific antibodies to fibronectin indicate the cartilagenous primordia prior to overt chondrogenesis. Given the apparent nonequivalence of embryonic cartilages, the purpose of this study was to determine whether this phenomenon was unique to developing chick limbs or is a more general characteristic of chondrogenesis. The appearance and distribution of fibronectin during chick first and second branchial arch development in ovo was investigated by indirect immunofluorescence techniques in H.H. stages 15-26. Fibronectin can be detected in early stages in areas presumed to be composed mainly of ectomesenchyme. During later stages of development, successive nonrandom patterns of fibronectin distribution appear to precede overt chondrogenesis as demonstrated by alcian blue staining. Pretreatment of cartilage with testicular hyaluronidase, prior to fibronectin staining, revealed that fibronectin was still present, suggesting that it was masked by proteoglycans. Fibronectin was also detected in the developing membrane bones of the mandible. The nonrandom patterning of fibronectin distribution in ovo in chick branchial arches and limb buds, respectively derived from neural crest and somatic mesoderm, were similar. It appears that specific patterns of fibronectin distribution were characteristic of chondrogenesis, regardless of the embryonic origin of the cartilage. This phenomenon may prove to be an extremely useful probe for early developmental skeletal abnormalities.

Animals↗

PubMedDate not supplied

H-2 haplotype and heterochronic orofacial morphogenesis in congenic mice: consideration as a possible explanation for differential susceptibility to teratogenesis.

For over 40 years it has been known that genetically different inbred strains of mice have different degrees of susceptibility to corticosteroid-induced cleft palate. Gene(s) at or near the H-2 region on chromosome 17 have been implicated. One postulated explanation is that the strain difference in susceptibility is not related to differential corticosteroid action, but to differences in normal developmental pattern. Studies have demonstrated significant quantitative differences between inbred strains for a number of growth variables relative to palatal development. It is also known that there are genes at or near the H-2 complex that influence pre- and post-implantation development. Thus, we sought to determine the relationship in H-2 congenic mice between haplotype differences and variation in normal orofacial development. Morphometric analyses of the palatal region in serially sectioned E13 and E17 B10 and B10.A mice were completed. We were able to find some evidence for H-2 haplotype related phenotypic differences, but these differences are less than compelling as an explanation for haplotype-dependent susceptibility differences. A more likely explanation is GR-mediated differential corticosteroid responsiveness and its consequent effects on palatal shelf growth.

Adrenal Cortex Hormones↗

PubMedDate not supplied

The CORT-GR signal transduction pathway and CORT-induced cleft palate in H-2 congenic mice.

A significant association between genes at or near the H-2 complex and glucocorticoid (CORT)-induced cleft palate in mice has been conclusively demonstrated. In addition, the frequency of CORT-induced cleft palate in heterozygous offspring from reciprocal crosses has been shown to be dependent on maternal H-2 haplotype. Although CORT responses are known to be mediated through the glucocorticoid receptor (GR), the involvement of H-2 haplotype-specific variation in the embryonic CORT-GR signal transduction pathway in CORT responsiveness remains uncertain. In this study, we characterized the embryonic (E13 to E15) CORT-GR pathway in developing B10 (H-2b) and B10.A (H-2a) mouse palates. Northern analysis demonstrates similar GR transcripts and mRNA steady-state levels in embryonic B10 and B10.A mouse palates. Palatal GR M(r) and pI, as determined by Western analysis, are similar between strains and among gestational days. We also analyzed possible haplotype-specific qualitative or quantitative differences in the ability of the GR to bind a glucocorticoid response element (GRE); no significant differences in the GR-GRE complex or in the levels of activated GR are seen between strains or among gestational days. Based on these results, we conclude that H-2 associated differences in susceptibility to CORT-induced cleft palate are not associated with either variation in embryonic GR or increasing gestational age. To determine if endogenous differences in maternal circulating corticosterone levels are related to differential embryonic CORT responsiveness, the levels of serum corticosterone were determined by RIA in pregnant dams on day 13 of gestation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Glucocorticoids, TGF-beta, and embryonic mouse salivary gland morphogenesis.

Branching morphogenesis is a fundamental embryologic process in many developing organs: salivary gland, lung, pancreas, mammary gland, and kidney. Glucocorticoids (CORT) are known to regulate morphogenesis in several branching organs (e.g., lung); we hypothesize that CORT is also important to embryonic mouse salivary gland morphogenesis. We studied the CORT-glucocorticoid receptor (GR) signal transduction pathway during embryonic mouse submandibular gland development. Western analysis demonstrates that the 96-kDa GR is present in E14 to E18 submandibular glands. The embryonic GR is functional, as defined by its ability to bind a DNA CORT response element, for all gestational ages evaluated (E14 to E18); increasing GR levels are observed with progressive development. The level of endogenous corticosterone in embryonic submandibular glands was also determined. Using radioimmunoassays corticosterone is first detected on day 15 of gestation; there is a progressive increase in steroid levels from day 15 to 18 of gestation. In addition, we investigated the effect of exogenous CORT on submandibular gland morphogenesis in vivo and in vitro. In vivo experiments were performed using maternal injection of CORT or sham injection on day 12 of gestation with sacrifice 72 hr post-injection (E15). CORT treatment significantly increases embryonic submandibular gland growth in vivo. To further analyze the effect of exogenous CORT on embryonic submandibular gland morphogenesis, E13 mouse submandibular glands were cultured under serum-free, chemically-defined conditions. A significant (P < 0.05) enhancement of mean branching ratios (72 hr/0 hr) is detected in CORT-supplemented explants (10(-5) M to 10(-8) M) compared to control explants; doses more dilute than 10(-8) M CORT do not significantly (P > 0.10) increase the induction of branching. In addition, CORT administration to embryonic mice in utero enhances the expression of acinar-cell-specific mucin protein. These data indicate that the CORT-GR signal transduction pathway plays an important role in salivary gland morphogenesis. Northern analysis of TGF-beta 1, TGF-beta 2, and TGF-beta 3 transcript levels in vivo confirms the presence of TGF-beta 1 and TGF-beta 2 and identifies TGF-beta 3 in embryonic submandibular glands. To begin to identify a molecular mechanism of CORT-GR mediated submandibular gland morphodifferentiation, we studied the effect of CORT on growth factor gene expression, specifically TGF-beta. Northern analysis suggests that the CORT-GR signal transduction pathway modulates the rate of morphogenesis by regulating TGF-beta 2 and TGF-beta 3 mRNA expression.

Analysis of Variance↗

PubMedDate not supplied

Msx-2 expression and glucocorticoid-induced overexpression in embryonic mouse submandibular glands.

It is well known that the process of branching morphogenesis requires epithelial-mesenchymal interactions. One outstanding model for the study of tissue interactions during branching morphogenesis is the embryonic mouse submandibular gland (SMG). Although it has been clearly demonstrated that the branching pattern is dependent on interactions between the epithelium and the surrounding mesenchyme, little is known about the molecular mechanism underlying the branching process. One group of transcription factors that likely participates in the control of epithelial-mesenchymal inductive interactions are the Msx-class of homeodomain-containing proteins. In this paper, we focus on Msx-2 because its developmental expression is correlated with inductive interactions, suggesting that Msx-2 may play a functional role during cell-cell interactions. We demonstrate the expression of Msx-2 mRNA and protein to be primarily in the branching epithelia with progressive embryonic (E13 to E15) SMG development and, to a lesser extent, in the mesenchyme. We also show that Msx-2 is expressed by embryonic SMG primordia cultured under defined conditions. In addition, to begin to delineate a functional role for Msx-2, we employed an experimental strategy by using exogenous glucocorticoid (CORT) treatment of embryonic SMGs in vitro and in vivo to significantly enhance branching morphogenesis and evaluate the effect of CORT treatment on embryonic SMG Msx-2 expression. A marked increase in Msx-2 transcripts and protein is detected with in vitro and in vivo CORT treatment. Our studies indicate that one mechanism of CORT regulation of salivary gland morphogenesis is likely through the modulation of Msx-2 gene expression.

Animals↗