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T D Stephens

Publications and source records attributed to T D Stephens.

At least 19 recordsLinked to original sources
PubMed2000

Mechanism of action in thalidomide teratogenesis.

In this commentary, we describe a model to explain the mechanism of the embryopathy of thalidomide. We propose that thalidomide affects the following pathway during development: insulin-like growth factor I (IGF-I) and fibroblast growth factor 2 (FGF-2) stimulation of the transcription of alphav and beta3 integrin subunit genes. The resulting alphavbeta3 integrin dimer stimulates angiogenesis in the developing limb bud, which promotes outgrowth of the bud. The promoters of the IGF-I and FGF-2 genes, the genes for their binding proteins and receptors, as well as the alphav and beta3 genes, lack typical TATA boxes, but instead contain multiple GC boxes (GGGCGG). Thalidomide, or a breakdown product of thalidomide, specifically binds to these GC promoter sites, decreasing transcription efficiency of the associated genes. A cumulative decrease interferes with normal angiogenesis, which results in truncation of the limb. Intercalation into G-rich promoter regions of DNA may explain why certain thalidomide analogs are not teratogenic while retaining their anti-tumor necrosis factor-alpha (TNF-alpha) activity, and suggests that we look elsewhere to explain the action of thalidomide on TNF-alpha. On the other hand, the anti-cancer action of thalidomide may be based on its antiangiogenic action, resulting from specific DNA intercalation. The tissue specificity of thalidomide and its effect against only certain neoplasias may be explained by the fact that various developing tissues and neoplasias depend on different angiogenesis or vasculogenesis pathways, only some of which are thalidomide-sensitive.

Animals↗
PubMed2000

Hypothesis: thalidomide embryopathy-proposed mechanism of action.

We propose that thalidomide affects the following pathway during limb development: Growth factors (FGF-2 and IGF-I) attach to receptors on limb bud mesenchymal cells and initiate some second messenger system (perhaps SP-1), which activates alphav and beta3 integrin subunit genes. The resulting alphav beta3 integrin proteins stimulate angiogenesis in the developing limb bud. Several steps in this pathway depend on the activation of genes with primarily GC promoters (GGGCGG). Thalidomide, or a hydrolysis or metabolic breakdown product, specifically binds to GC promoter sites and inhibits the transcription of those genes. Inhibition of the genes interferes with normal angiogenesis, which results in truncation of the limb.

Abnormalities, Drug-Induced↗
PubMed1999

Paraxial and lateral plate influences on reinitiation of wing development in chicken embryos.

Stephens et al. ([1993] Dev. Dynam. 197:157-168) hypothesized that the chick embryo wing territory is not an equipotential system. They proposed that following extirpation of the wing territory, limb formation is reinitiated, stimulated by more paraxial tissues. It was the purpose of this study to test this hypothesis. Four sets of procedures were undertaken in stage 11-12 chick embryos: 1) the wing territory lateral plate was removed (negative controls); 2) medial (between the central axis and somites), lateral (between the mesonephros and lateral plate), and intermediate (between the somites and mesonephros) foil barriers were placed adjacent to the wing territory (positive controls); 3) barriers were placed as above, with the removal of the lateral plate (experimental); and 4) barriers were placed lateral to the area of lateral plate extirpation (experimental). Normal limbs developed in 89% of the embryos without foil barriers with the lateral plate removed. In 93% of the embryos that contained medial barriers, normal wings developed whether or not the limb territory was extirpated, and in 100% of the embryos with intermediate or lateral barriers, with or without extirpation, deficient limbs occurred. When foil barriers were placed lateral to the wound, 87% of the chick wings were either reduced or absent. Closure of the wound following extirpation appeared to progress from lateral to medial. The data from this study appear to support the hypothesis that the limb territory is not equipotential but is reformed from cells closing the wound from lateral to medial, and is reinitiated from paraxial tissues (medial to lateral) following wound healing.

Animals↗
PubMed1996

Lability of the presumptive pectoral and pelvic girdle territories compared using celomic grafts.

The concept of "limbness" usually implies "wingness" or "legness". We present evidence in this study that in the case of the proximal forelimb, limbness may exist independent of wingness. Presumptive wing and leg regions were grafted into the opposite limb (wing into leg or leg into wing) of stage 18 hosts. Several stage 10+ to 11+ presumptive wing regions grafted into host legs developed pelvic girdles associated with distal wing elements. This phenomenon was not seen in presumptive wing region grafts older than stage 12-. Presumptive leg regions grafted into host wings developed leg structures only, including pelvic girdle and leg digits. The pectoral girdle appears to be labile in early stages, whereas the pelvic girdle is not labile even during early stages.

Animals↗
PubMed1996

Mesonephros has a role in limb development and is related to thalidomide embryopathy.

Recent studies have demonstrated a link between limb reduction defects and mesonephros removal [Geduspan and Solursh, 1992) Dev. Biol., 151:242-250]. However, there is some question as to whether the limb-reduction defects seen in that study resulted from the removal of mesonephros or from the formation of scar tissue medial to the limb territory. The current study was conducted to test the hypothesis that elimination of the mesonephros without producing scar tissue adjacent to the limb will adversely affect limb morphogenesis. The hypothesis was tested by the insertion of tantalum foil barriers into various levels of the intermediate mesoderm of developing chick embryos to prevent the caudal elongation of the mesonephros. Limb reduction defects were obtained when the mesonephros was prevented from forming caudal to somite 14. No limb defects were seen when a foil barrier was placed into the intermediate mesoderm at the level of somite 21 or 25. Our results support the notion that a signal from the mesonephros is necessary for normal limb development. In addition, it appears that a craniocaudal factor emanating from the mesonephros plays a role in limb development. The limb reduction defects obtained in this study were also compared to the pattern of thalidomide embryopathy in humans. There is a close correspondence between the types of limb reduction anomalies seen with thalidomide and mesonephric blocks and between the severity of defects vs. the timing of thalidomide intake or mesonephric blockage. A model for possible thalidomide embryopathy is presented.

Animals↗
PubMed1993

Evaluation of the chick wing territory as an equipotential self-differentiating system.

Harrison (1918: J. Exp. Zool. 25: 413-461) described a developmental field as an "equipotential self-differentiating system." The present study was undertaken to address the question: To what extent can be pre-limb territory of a chick embryo be considered a developmental field? To what extent is the chick pre-limb territory an equipotential self-differentiating system? Two sets of experiments were undertaken to address these questions: (1) Whole and half limb territories were explanted to the celoma of host embryos, and (2) portions of the wing territories were extirpated. The wing exhibited the quality of self-differentiation after stage 12, in that the isolated wing territory, grafted to a host celom, could form limbs beginning at stage 12 (however, complete wings formed only from wing territories of stage 16 and older). On the other hand, the chick wing territory did not appear to exhibit equipotentiality. No posterior half limb graft formed normal limbs, and only in two exceptional cases did anterior half limb grafts form limbs. If part or all of the wing territory was removed from chick embryos, normal limbs formed in less than 15% of the cases after stage 15, in about 30% of the cases at stages 13 and 14, but in over half the cases at stages 10-12. Wound healing and reinitiation of limb potential may be responsible for the higher incidence of limb formation at the younger ages.

Animals↗
PubMed1992

Visual demonstration of the limb-forming zone in the chick embryo lateral plate.

The present study was undertaken to determine whether a visible Wolffian ridge, distinct from the lateral fold, can be identified in chick embryos. Ectoderm thickness was measured in stage 11-17 chick embryos. There was a general trend, from thin ectoderm in the midline, to an ectodermal thickening over the somites, intermediate mesoderm, and lateral plate. Other embryos were cut from the yolk, pinned out, and photographed. The lateral fold was then eliminated, and the embryo was rephotographed. The photographs reveal a definite opaic zone, distinct from the lateral fold, in stage 11-18 chick embryos. Furthermore, there is a direct correlation between the opacity of this cellular band and the limb-forming potential of grafted wing, flank, and leg regions (see Stephens et al., '89). At stages 11-14, the wing, flank, and leg exhibit a uniform opacity, and a uniform capacity for limb formation when grafted to a host celom. From stage 15 to stage 18, the opacity in the flank diminishes, and its limb-forming capability disappears. This study demonstrates the presence of an opaic zone, which we have called the limb-forming zone (LFZ) along the lateral side of early chick embryos, which is independent of the lateral fold, is not as extensive as the lateral plate, and is not simply associated with ectodermal thickening, but which is directly correlated with limb-forming potential in the lateral plate.

Animals↗
PubMed1991

Review of drug-induced limb defects in mammals.

The objective of this paper was to illustrate the spectrum of possible limb malformations in mammals resulting from drug exposure. A bibliography of 171 papers from 20 journals was generated from which pertinent data (drug used, limb defects reported, predominant defect location) were tabulated. These data should provide a basis for predictions about types of defects that might be expected in further studies and for judging postulated drug-induced human limb defects. However, direct extrapolation to humans is inappropriate. The following trends were observed: 1) Distal limb defects (autopod) are almost twice as common as proximal limb defects (stylopod and zygopod). 2) Ectrodactyly is the single most common type of limb defect, accounting for over half of the autopod defects. 3) Ectrodactyly is almost twice as common in the hindlimb as in the forelimb. 4) Postaxial ectrodactyly is over twice as common as preaxial ectrodactyly in the forelimb, but preaxial ectrodactyly is four times more common in the hindlimbs. 5) Polydactyly occurs with approximately equal frequency in forelimbs and hindlimbs, and preaxial polydactyly is most common in both fore and hindlimbs. 6) Polymelia (supernumerary limbs) occurred in one case, and may have been a spurious result. 7) Either transverse hemimelia is greatly underreported in teratology studies or it essentially does not occur. We have concluded that, at least in some cases, acetazolamide, adenine, 1,7-dimethylxanthine, and xanthine derivative aminophylline, retinoic acid, acetoxy-methyl-methylnitrosamine, aspirin, and cadmium can all cause unilateral defects.

Abnormalities, Drug-Induced↗
PubMed1989

Fetus amorphus or placental teratoma?

A differential diagnosis between fetus amorphus and placental teratoma based on the presence of an umbilical cord and/or skeletal organization in the fetus amorphus has been proposed (Fox and Butler-Manual: Journal of Pathology 88:137-140, 1964). We report a description of one new case of fetus amorphus, along with the results of a critical reexamination of 96 cases from the literature. Our findings fail to support the proposed criteria for distinguishing fetus amorphus from placental teratomas. We find that the presence or absence of an umbilical cord does not relate at all to the developmental state of the specimen. The extent of skeletal development may be a more valid criterion; however, the internal organization in the fetus amorphus forms an anatomical continuum with that of the placental teratoma, making a differential diagnosis meaningless. Additional research is necessary to solve this dilemma.

Abnormalities, Severe Teratoid↗
PubMed1989

Limbness in the early chick embryo lateral plate.

In order for the limb to be useful in the evaluation of early determinants of morphogenesis, it is necessary to understand some of the characteristics associated with "limbness" and, more importantly at the beginning at least, it is necessary to know what regions of the early embryo exhibit limbness qualities. Previous investigators have assumed, without direct experimental evidence, that the flank does not have limbness qualities, even at early stages of development. However, there are a few studies suggesting that the early flank does possess limbness qualities. The purpose of the present study was to determine how extensively the qualities of limbness exist in the early chick embryo. Tissues from the future neck, wing, flank, and leg regions were grafted to host celoms and evaluated for their abilities to form limbs. Limbs developed from all four regions of stage 11-14 embryos, but after stage 14 only grafts from the wing and leg regions formed limbs.

Animals↗
PubMed1988

A method for predicting the cranio-caudal position of secondary embryonic structures.

The morphogenetic events that give rise to a specific body pattern have to date avoided extensive elucidation. Extant models of pattern formation have dealt almost exclusively with the "primary patterning" of structures in the embryo. These "universal" models fail to explain many morphological conditions, such as the simultaneous change in position of the limbs, celom, mesonephros, and umbilical artery relative to the somites as a result of a single mutation. In the present paper, we propose that the relation between two non-periodic waves may function to determine the position of "secondary structures", such as the limbs, in the embryo, relative to primary structures such as the somites. We propose that if two morphogenetic events are initiated at different times from the same region of the embryo, and are progressing in a cranio-caudal sequence at different rates, then the location of a given structure along the body axis can be described as a function of the two events. Applications and predictions based on the proposal are presented. Evidence from observations of morphogenetic events in the chick embryo, which tend to support the model, are also presented.

Animals↗
PubMed1984

Muscle abnormalities associated with the twin reversed-arterial-perfusion (TRAP) sequence (acardia).

Even though over 400 acardia (twin reversed-arterial-perfusion, TRAP) specimens have been reported in the literature since 1533, few attempts have been made to provide detailed evaluation of anything other than the circulation. The purpose of this study was to evaluate the various limb defects in nine TRAP specimens in light of the presumed etiology and pathogenesis, reversed arterial perfusion, and subsequent degenerative changes in the fetus. Two hypotheses were tested: (1) degeneration of formed tissues should not result in tissue rearrangement and (2) one tissue type should be lost in preference to the others. Neither of these hypotheses were supported by the data. Alternative explanations are discussed as well as the implications of these observations on the concept of reversed arterial perfusion.

Diseases in Twins↗
PubMed1983

Muscle abnormalities associated with radial aplasia.

The purpose of this paper was to report the muscle variations in eleven cases of radial aplasia and to extract information relative to normal and abnormal limb muscle development. The cases all involved other defects ranging from acardia to "thrombocytopenia-absent radius" (TAR) and included several multiple malformations. The muscle patterns did not seem to depend upon the etiology of the radial aplasia but appeared to be more dependent upon late embryonic or early fetal muscular repositioning.

Abnormalities, Multiple↗