Biomedical subjects

D A Sassoon

Publications and source records attributed to D A Sassoon.

11 recordsLinked to original sources

PubMed1992

Myogenesis in the mouse.

The first striated muscle to form during mouse embryogenesis is the heart followed by skeletal muscle which is derived from the somites. The expression of genes encoding muscle structural proteins and myogenic regulatory sequences of the MyoD1 family has been examined using 35S-labelled riboprobes. In the cardiac tube, actin and myosin genes are expressed together from an early stage, whereas in the myotome, the earliest skeletal muscle, they are activated asynchronously over days. They are not expressed in the somite prior to myotome formation. One potential muscle marker, carbonic anhydrase III, is expressed in early mesoderm and subsequently in the notochord, similarly to the Brachyury gene. The myogenic sequences are not detectable in the heart. In the myotome they show distinct patterns of expression; this is discussed in the context of their role as muscle transcription factors. myf-5 is the only myogenic factor sequence present in the somite prior to muscle formation and thus is potentially involved in an earlier step of muscle determination. It is also present in the early limb bud, but the status of myogenic precursor cells in the limb in this context is less clear.

Actins↗

PubMed1992

Id expression during mouse development: a role in morphogenesis.

We have characterized the spatial and temporal pattern of Id transcription during mouse embryogenesis. The Id gene encodes a helix-loop-helix (HLH) protein which can heterodimerize with the ubiquitously expressed HLH protein products of the E2A gene, and prevent them from binding DNA either alone or as a heterodimer with tissue specific HLH transcription factors such as the muscle determination gene, MyoD1 (Benezra et al., 1990: Cell 61:49-59). Since Id has been shown to be down-regulated during induced differentiation in several cell lines, it has been postulated that Id plays a general inhibitory role in cell differentiation (Benezra et al., 1990). In situ analysis of Id mRNA expression in the mouse embryo was performed in order to determine whether the pattern of Id expression is consistent with this postulate. A detailed study throughout the entirety of mouse postimplantation development reveals that Id is expressed upon gastrulation at very high levels in almost all regions of the mouse embryo and expression declines as embryogenesis proceeds. In skeletal muscle, in which the inhibitory action of Id has been established in tissue culture models (Benezra et al., 1990), Id and the HLH myogenic factors are expressed in a mutually exclusive manner suggesting that myogenic precursors do not express both types of HLH gene products. In addition, Id colocalizes both spatially and temporally with Hox-7.1, a murine homeobox gene which is associated with regions of high cell proliferation and positional fate assignment.

Animals↗

PubMed1992

Loss of N-myc function results in embryonic lethality and failure of the epithelial component of the embryo to develop.

myc genes are thought to function in the processes of cellular proliferation and differentiation. To gain insight into the role of the N-myc gene during embryogenesis, we examined its expression in embryos during postimplantation development using RNA in situ hybridization. Tissue- and cell-specific patterns of expression unique to N-myc as compared with the related c-myc gene were observed. N-myc transcripts become progressively restricted to specific cell types, primarily to epithelial tissues including those of the developing nervous system and those in developing organs characterized by epithelio-mesenchymal interaction. In contrast, c-myc transcripts were confined to the mesenchymal compartments. These data suggest that c-myc and N-myc proteins may interact with different substrates in performing their function during embryogenesis and suggest further that there are linked regulatory mechanisms for normal expression in the embryo. We have mutated the N-myc locus via homologous recombination in embryonic stem (ES) cells and introduced the mutated allele into the mouse germ line. Live-born heterozygotes are under-represented but appear normal. Homozygous mutant embryos die prenatally at approximately 11.5 days of gestation. Histologic examination of homozygous mutant embryos indicates that several developing organs are affected. These include the central and peripheral nervous systems, mesonephros, lung, and gut. Thus, N-myc function is required during embryogenesis, and the pathology observed is consistent with the normal pattern of N-myc expression. Examination of c-myc expression in mutant embryos indicates the existence of coordinate regulation of myc genes during mouse embryogenesis.

Alleles↗

PubMed1992

MHox: a mesodermally restricted homeodomain protein that binds an essential site in the muscle creatine kinase enhancer.

Myogenic helix-loop-helix (HLH) proteins, such as myogenin and MyoD, can activate muscle-specific transcription when introduced into a variety of nonmuscle cell types. Whereas cells of mesodermal origin are especially permissive to the actions of these myogenic regulators, many other cell types are refractory to myogenic conversion by them. Here we describe a novel homeodomain protein, MHox, that binds an A+T-rich element in the muscle creatine kinase (MCK) enhancer that is essential for muscle-specific transcription and trans-activation by myogenic HLH proteins. MHox is completely restricted to mesodermally derived cell types during embryogenesis and to established cell lines of mesodermal origin. In contrast to most other homeobox genes, MHox expression is excluded from the nervous system, with the highest levels observed in limb bud and visceral arches. In adult mice, MHox is expressed at high levels in skeletal muscle, heart and uterus. The DNA-binding properties and pattern of MHox expression are unique among homeobox genes and suggest a role for MHox as a transcriptional regulator that participates in the establishment of diverse mesodermal cell types.

Amino Acid Sequence↗

PubMed1991

Expression of the muscle regulatory factor MRF4 during somite and skeletal myofiber development.

The muscle regulatory factors MRF4, myogenin, myf-5, and MyoD constitute a family of proteins that can function as muscle-specific transcriptional activators. Although this gene family has been extensively studied, a specific role for each factor during myogenesis remains to be determined. Understanding how these factors function requires a detailed analysis of their expression patterns during development. Toward this goal, we examined the temporal pattern of expression of MRF4 and the other factors in the rat myogenic cell line L6J1-C, in newborn rat primary muscle cell cultures and in fetal and postnatal rat limb muscle. Our results demonstrate that MyoD, myogenin, and myf-5 transcripts accumulate maximally at various stages of myoblast differentiation and decline to low expression levels in adult muscle tissue. In contrast, MRF4 transcript accumulation is restricted to cell cultures containing multinucleate myofibers, and its expression in vivo increases sharply during late fetal muscle development. This level of MRF4 expression is maintained in the adult which, together with decreased expression of the other three muscle regulatory factors, makes MRF4 the predominant factor in adult muscle. In situ hybridization of mouse embryo tissue sections indicates that MRF4 transcripts accumulate in the limb beginning 13.5 days post coitum, which is 2 days later than the initial appearance of myogenin and MyoD transcripts. Hybridization to earlier stages of development reveals, however, that MRF4 mRNA initially is present in the myotomal compartment of the somites, just after myogenin but 2 days prior to MyoD expression. Unlike myogenin and MyoD, MRF4 expression declines in the myotomes at the time that multinucleate axial muscles begin to form in this region, although during later development MRF4 is expressed in the myofibers of axial muscles at levels comparable to those in the limb. Differences in the expression patterns for MRF4, myogenin, myf-5 and MyoD between myotomal and other skeletal muscle development suggest that the relative timing of expression for each muscle regulatory factor may control the distinct phenotypes associated with myotomal myocytes and multinucleate myofibers.

Aging↗

PubMed1990

Perinatal outcome in triplet versus twin gestations.

The present study was conducted to determine whether triplet pregnancies are associated with a significantly worse perinatal outcome than twin pregnancies. Maternal and neonatal outcome was evaluated in 15 triplet and twin pregnancies that were matched for maternal age, race, type of medical insurance, delivery mode, parity, and history of previous preterm delivery. Preterm labor occurred significantly more often in triplet than in twin gestations (80 versus 40%), as did preterm delivery (87 versus 26.7%). Triplets had a significantly lower mean birth weight (1720 versus 2475 g) and gestational age at delivery (33 versus 36.6 weeks). In addition, 53.3% of triplet pregnancies but only 6.7% of twin pregnancies had one or more neonates with intrauterine growth retardation. Discordancy also occurred more frequently in triplets than in twins (66.7 versus 13.3%). The mean averaged neonatal hospital stay was significantly higher in triplets (29 versus 8.5 days), and triplets had a fivefold increased risk of requiring neonatal intensive care as compared with twins. However, there were no significant differences between the groups in maternal morbidity or major neonatal complications such as respiratory distress syndrome or intraventricular hemorrhage. We believe that these data will be useful in counseling patients with respect to the anticipated perinatal outcome of triplet pregnancies.

Adult↗

PubMed1990

The biophysical profile in labor.

To determine whether the biophysical profile would be a valuable intrapartum addition to fetal heart rate monitoring in predicting umbilical arterial acid-base status at delivery, 95 patients at term had serial studies during labor and umbilical artery blood gas analysis. There was no significant association between biophysical profile score and cord blood pH, nor was there a difference in scores between the acidemic and nonacidemic groups. Of the five components of the initial biophysical profile, only a nonreactive nonstress test (NST) was associated with both pH 7.20 or less (P = .019) and metabolic acidemia (P = .016). None of the individual variables of the final examination correlated with a pH of 7.20 or less. However, a nonreactive NST was associated with metabolic acidemia (P = .03), as was the presence of breathing (P = .03). Of the ten infants with pH 7.20 or less, eight had an initial and five had a final biophysical profile score of 8 or higher. Of the five whose pH was less than 7.15, four had an initial and three a final score of 8 or more. Finally, of the five with metabolic acidemia, four had an initial and two a final score of 8 or higher. Half of the acidemic fetuses had final biophysical profile scores of 8 or higher, suggesting that this score in labor is not reliable to rule out acidemia at delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1989

Myogenin, a factor regulating myogenesis, has a domain homologous to MyoD.

In this report, we describe the isolation, sequence, and initial characterization of the cDNA for the muscle-specific regulatory factor skeletal myogenin. Transfection of myogenin into the mesenchymal cell line C3H10T1/2 produces cells expressing muscle-specific markers. Myogenin is absent in undifferentiated cells, peaks, and then declines following a stimulus to differentiate, and is overexpressed in myoblasts selected with 5-bromodeoxyuridine for the overproduction of factors that regulate the decision to differentiate. High levels of myogenin transcripts are present in the myotomal region of somites at 8.5 days of gestation in the mouse. Although myogenin and MyoD are different genes, they share the myc homology domain. Myogenin and MyoD thus form part of a gene family regulating myogenesis, and together with myd may constitute a set of factors that interact to regulate the determination and differentiation of muscle cells.

Amino Acid Sequence↗

PubMed1989

Perinatal factors influencing atrial natriuretic peptide levels in umbilical arterial plasma at the time of delivery.

Little is known about atrial natriuretic peptide metabolism or secretion in the human fetus. The purpose of this study was to determine if both the placenta and umbilical vessels are possible sites of atrial natriuretic peptide metabolism and to evaluate the effects that labor, route of delivery, prolonged pregnancy, preeclampsia, and fetal distress have on umbilical arterial atrial natriuretic peptide levels. We found that plasma atrial natriuretic peptide levels in the umbilical artery are significantly greater than those in the vein (p less than 0.001). Umbilical arterial and umbilical venous atrial natriuretic peptide levels were higher in plasma samples collected immediately at delivery when compared with those obtained 10 minutes later (p less than 0.001). Umbilical arterial atrial natriuretic peptide levels were elevated in pregnancies complicated by preeclampsia and fetal distress (p less than 0.01). Labor, route of delivery, and prolonged pregnancy had no effect on umbilical arterial atrial natriuretic peptide levels. We propose that both the placenta and umbilical vessels contain atrial natriuretic peptide receptors that are involved in the clearance or metabolism of atrial natriuretic peptide. The increased umbilical arterial atrial natriuretic peptide levels present in preeclampsia and fetal distress may reflect an attempt by the fetus to regulate blood flow.

Atrial Natriuretic Factor↗

PubMed1988

Transcripts of alpha-cardiac and alpha-skeletal actins are early markers for myogenesis in the mouse embryo.

Among the first tissues to differentiate in the mammalian embryo are cardiac and subsequently skeletal striated muscle. We have developed specific cRNA probes corresponding to the 5' noncoding regions of alpha-cardiac and alpha-skeletal actin mRNAs in order to investigate myogenesis in the mouse embryo. Transcripts coding for cardiac actin which is the major isoform of the adult heart can first be detected between 7.5 and 7.8 days p.c. in the developing heart and are observed in all somites as they are formed. In addition, alpha-skeletal actin transcripts are accumulated at much lower levels in cardiac tissue and newly formed somites; both heart and skeletal muscle show co-expression of this actin gene pair at all stages of development examined. The fact that cardiac actin transcripts can be observed in the myotomal portion of the somite prior to muscle fibre differentiation indicates that cardiac actin transcripts (and to a lesser extent skeletal actin transcripts) are markers not only of striated muscle tissue, but also of earlier stages of the myogenic programme in vivo.

Actins↗

PubMed1987

Androgen regulation of muscle fiber type in the sexually dimorphic larynx of Xenopus laevis.

We used histochemical techniques [assays for adenine triphosphatase (ATPase) and succinate dehydrogenase (SDHase) activity] to identify muscle fiber types in the larynx of Xenopus laevis. Male muscle is made up of one fiber type, medium-sized fibers (approximately 9 microns2) that stain lightly for acid-stable ATPase and intensely for SDHase activity. In contrast, the female has 3 fiber types: small fibers (approximately 6 microns2) that stain intensely for ATPase and SDHase, medium-sized fibers (approximately 13 microns2) with moderate staining for ATPase and dark staining for SDHase, and large fibers (approximately 15 microns2) with little SDHase or ATPase activity. Long-term castration (6 months) has no effect on histochemical staining of adult male fibers. Long-term testosterone treatment (5 months) increases the proportion of medium-sized, moderately staining fibers in adult females, and reduces the proportion of both the small, darkly staining fibers and the large, lightly staining fibers. At metamorphosis, both males and females have 3 fiber types whose ATPase activity is similar to that of the adult female. However, no SDHase activity is observed. Treatment of juveniles for 3 weeks with testosterone results in nearly complete masculinization of muscle fibers, as judged by increased cross-sectional area, homogeneous ATPase staining, and a marked increase in SDHase activity. Thus, juvenile muscle is considerably more responsive to testosterone than is adult female muscle. We propose that the uniform metabolic properties of male laryngeal muscle contribute to the production of the rapid (66 Hz) mate call vocalizations characteristic of this species. Further, our results suggest that androgens direct the masculinization of laryngeal muscle fibers during postmetamorphic development.

Androgens↗