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PubMed1999

Alcohol promotes in vitro chondrogenesis in embryonic facial mesenchyme.

Ethanol is a well-recognized teratogen in vertebrates that can perturb the development of the facial primordia and various other embryonic structures. However,the mechanisms underlying alcohol's effects on embryogenesis are currently unclear. Recent evidence suggests that the cranial neural crest, which forms the entire facial skeleton, may be a particularly sensitive target of ethanol teratogenicity. In the present study we have examined the influence of in vitro ethanol exposure on cartilage differentiation in micromass cultures of mesenchymal cells isolated from the various facial primordia (maxillary, mandibular, frontonasal, and hyoid processes) of the stage 24 chick embryo. In all four populations of facial mesenchyme, exposure to 1-1.5% ethanol promoted marked increases in Alcian blue-positive cartilage matrix formation, a rise in 35SO4 accumulation into matrix glycosaminoglycans, and enhanced expression of cartilage-characteristic type II collagen and aggrecan gene transcripts. In frontonasal and mandibular mesenchyme cultures, which undergo extensive spontaneous cartilage formation, ethanol treatment quantitatively elevated both matrix production and cartilage-specific gene transcript expression. In cultures of maxillary process and hyoid arch mesenchyme, which form little or no cartilage spontaneously, ethanol exposure induced the formation of chondrogenic cell aggregates and the appearance of aggrecan and type II collagen mRNAs. These actions were not restricted to ethanol, since tertiary butanol treatment also enhanced cartilage differentiation in facial mesenchyme cultures. Our findings demonstrate a potent stimulatory effect of alcohol on the differentiation of prechondrogenic mesenchyme of the facial primordia. Further analysis of this phenomenon might yield insight into the developmental mechanisms underlying the facial dysmorphologies associated with embryonic ethanol exposure.

Aggrecans↗

PubMed1993

The ontogeny of the neural crest.

The neural crest is part of a larger embryonic structure, the neural folds, belonging to the neural primordium of the Vertebrate embryo. The neural fold is formed by the anterior and lateral ridges of the neural anlage, which fuse mediodorsally when the neural tube closes. Anteriorly, the epithelium of the neural fold does not convert into mesenchymal cells and yields Rathke's pouch, the olfactory organ and the epithelium of the mouth roof, of the upper lip and of the frontal region of the head. From the level of the diencephalon (at the level of the epiphysis) downwards the neural fold epithelium undergoes the epitheliomesenchymal transition and yields the neural crest cells which become later on highly diversified and form various structures and tissues throughout the body. A large amount of data have shown that the environmental cues exerted on crest cells both during their migration and when they have reached their target sites are critical in determining their fate. In order to understand the mechanisms through which environmental factors influence crest cell differentiation, the developmental capacities of single neural crest cells were investigated at different time points of their ontogeny. Single cell cultures of crest cells have revealed that already at the migratory stage the neural crest is made up of cells at different states of determination. In particular, the analysis of clones obtained from single cell cultures of cephalic migratory crest cells has shown that, although many clonogenic cells are multipotent to varying degrees, others are committed to give rise to one single derivative. Totipotent progenitors able to generate representatives of virtually all the phenotypes (neuronal, glial, melanocytic and mesectodermal) encountered in cephalic neural crest derivatives were also found. We proposed that they represent stem cells analogous to those which in the hemopoietic system generate the various types of blood cells. The neural crest stem cell gives rise to diverse progenitors that become progressively restricted in their potentialities according to an essentially stochastic mechanism while dividing during and after completion of the migration process. Similar cloning experiments of crest cells that have already reached their target organs, i. e. sensory ganglia or enteric plexuses, showed that the phenotypic repertoire expressed by crest-derived cells decreases with increasing embryonic age. Efforts are made to elucidate the nature of the factors which influence either the survival and/or the differentiation of neural crest cells in the various types of environments in which they evolve.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed2006

Overview of retinoid metabolism and function.

Retinoids (vitamin A) are crucial for most forms of life. In chordates, they have important roles in the developing nervous system and notochord and many other embryonic structures, as well as in maintenance of epithelial surfaces, immune competence, and reproduction. The ability of all-trans retinoic acid to regulate expression of several hundred genes through binding to nuclear transcription factors is believed to mediate most of these functions. The role of all-trans retinoic may extend beyond the regulation of gene transcription because a large number of noncoding RNAs also are regulated by retinoic acid. Additionally, extra-nuclear mechanisms of action of retinoids are also being identified. In organisms ranging from prokaryotes to humans, retinal is covalently linked to G protein-coupled transmembrane receptors called opsins. These receptors function as light-driven ion pumps, mediators of phototaxis, or photosensory pigments. In vertebrates phototransduction is initiated by a photochemical reaction where opsin-bound 11-cis-retinal is isomerized to all-trans-retinal. The photosensitive receptor is restored via the retinoid visual cycle. Multiple genes encoding components of this cycle have been identified and linked to many human retinal diseases. Central aspects of vitamin A absorption, enzymatic oxidation of all-trans retinol to all-trans retinal and all-trans retinoic acid, and esterification of all-trans retinol have been clarified. Furthermore, specific binding proteins are involved in several of these enzymatic processes as well as in delivery of all-trans retinoic acid to nuclear receptors. Thus, substantial progress has been made in our understanding of retinoid metabolism and function. This insight has improved our view of retinoids as critical molecules in vision, normal embryonic development, and in control of cellular growth, differentiation, and death throughout life.

Animals↗

PubMed1997

The role of sonic hedgehog in vertebrate development.

Members of the hedgehog family are important signalling molecules during embryonic development. One member, Sonic hedgehog, is expressed in embryonic structures such as the zone of polarizing activity in the posterior limb bud, the notochord, and the floor plate of the neural tube, where it plays a role in patterning of the embryo. Sonic hedgehog is synthesized as an inactive precursor which must be proteolytically cleaved and modified by the addition of a cholesterol moiety to become active as a signalling molecule. In this processing, the C-terminal region of Sonic hedgehog serves as both the endoprotease and a cholesterol transferase. The importance of cholesterol for Sonic hedgehog function may explain many of the profound developmental defects caused by perturbations of cholesterol metabolism. The receptor for Sonic hedgehog is Patched, a multi-pass transmembrane protein which forms a complex with Smoothened Mutations in Patched are associated with basal cell naevus syndrome, while mutations in Sonic hedgehog cause holoprosencephaly. Downstream targets of Sonic hedgehog signalling are transcription factors like Gli3, responsible for Greigs polycephalosyndactyly in humans and Hoxd13, responsible for polysyndactyly.

Animals↗

PubMed1990

The fine structure of the embryonic envelopes before and after hatching in bothriocephalids: physiological and ecological significance.

The fine structure and differentiation of the embryonic envelopes before and after hatching in two bothriocephalid species of teleostean fish are described. Scanning electron microscopic observation of the egg surface confirmed the specific ornamentation of the capsule. Its thickness and topographic morphology reflect the physiocochemical characteristics of the environment. Beneath the eggshell, two syncytial layers were observed around the oncosphere. The outer envelope, visible during the preoncospheral phase, degenerated before the liberation of the coracidium. Glycoconjugate labelling confirmed the nutritive character of this layer. After hatching, the inner envelope was the only layer covering the oncosphere. The apical plasma membrane of the coracidial sheath bore cilia and numerous clublike microvilli. Beneath the cortical zone, the syncytial cytoplasm was vacuolated, resembling a honeycomb; the electron-dense zone, described from other pseudophyllideans, was not present. The basal membrane of the inner envelope, uniformly electron-dense, was assimilated by the oncospheral membrane. Comparison of the composition of the embryonic envelopes of pseudophyllideans with those of other tapeworm orders and trematodes revealed ontogenetic, structural and functional similarities between the embryotrophic layers. The physiological and ecological significance of the structure of the free-swimming coracidium is discussed. In this respect, the inner envelope around the oncosphere appears to be responsible for the inability of the larva to detect and invade the intermediate host.

Animals↗

PubMed1991

Cell lineage and cell migration in the neural crest.

The neural crest is a transient embryonic structure whose cells migrate extensively before giving rise to a variety of differentiated cell types. Both intrinsic cell lineage information and environmental cues are thought to play a role in determining the fate of these cells. Early in development, these cells can be divided into distinct populations based on their axial level of origin. Cranial neural crest cells differentiate into facial cartilage and cranial ganglia, whereas vagal crest cells give rise to the enteric ganglia. Trunk neural crest cells normally give rise to melanocytes, neurons, and glia of the peripheral nervous system and chromaffin cells of the adrenal medulla. Cell lineage studies of premigratory trunk neural crest cells using single cell injection of a vital dye have shown that single cells can give rise to a number of differentiated cell types. A host of extracellular matrix (ECM) molecules have been tested for their ability to support neural crest cell migration in vitro and in vivo. In general, the large glycoproteins (i.e., fibronectin and laminin) can support migration, whereas proteoglycans seem to modulate neural crest cell migration on other ECM molecules. However, no single molecule has been identified as the sole regulator of the complex pattern of neural crest cell migration.

Cell Adhesion↗

PubMed1993

Molecular regulation of neural crest development.

The neural crest is a transient embryonic structure that gives rise to a multitude of different cell types in the vertebrate. As such, it is an ideal model to study the processes of vertebrate differentiation and development. This review focuses on two major questions related to neural crest development. The first question concerns the degree and time of commitment of the neural crest cells to different cell lineages and the emerging role of the homeobox containing genes in regulating this process. Evidence from the cephalic crest suggests that the commitment process does start before the neural crest cells migrate away from the neural tube and gene ablation experiments suggest that different homeobox genes are required for the development of neural and mesenchymal tissue derivatives. However, clonal analysis of neural crest cells before migration suggests that many of the cells remain multi-potential indicating that the final determinative steps occur progressively during migration and in association with environmental influences. The second question concerns the nature of the environmental factors that determine the differentiation of neural crest cells into discrete lineages. Evidence is provided, mainly from in vitro experiments, that purified growth factors selectively promote the differentiation of neural crest cells down either sympathetic, adrenal, sensory, or melanocytic cell lineages.

Animals↗

PubMed2000

Cloning and expression of the Wnt antagonists Sfrp-2 and Frzb during chick development.

The Wnt genes are known to play fundamental roles during patterning and development of a number of embryonic structures. Receptors for Wnts are members of the Frizzled family of proteins containing a cysteine-rich domain (CRD) that binds the Wnt protein. Recently several secreted frizzled-related proteins (Sfrps) that also contain a CRD have been identified and some of these can both bind and antagonise Wnt proteins. In this paper we report the expression patterns of the chick homologues of Frzb, a known Wnt antagonist, and Sfrp-2. Both genes are expressed in areas where Wnts are known to play a role in development, including the neural tube, myotome, cartilage, and sites of epithelial-mesenchymal interactions. Initially, Sfrp-2 and Frzb are expressed in overlapping areas in the neural plate and neural tube, whereas later, they have distinct patterns. In particular Sfrp-2 is associated with myogenesis while Frzb is associated with chondrogenesis, suggesting that they play different roles during development. Finally, we have used the early Xenopus embryo as an in vivo assay to show that Sfrp-2, like Frzb, is a Wnt antagonist. These results suggest that Sfrp-2 and Frzb may function in the developing embryo by modulating Wnt signalling.

Amino Acid Sequence↗

PubMed1993

Morphological evidence for secondary formation of the tail gut in the rat embryo.

The secondary body formation is a developmental mechanism occurring in the caudal part of the embryo in which embryonic structures arise from a mass of mesenchymal cells without previous formation of germ layers. The formation of the tail gut by this mechanism was investigated on transverse serial semithin and ultrathin sections of 12-, 13-, 14- and 15-day rat embryo tails. The tail gut, together with the tail portion of the notochord, originates from an axial mass of condensed mesenchymal cells named tail cord. Formation of the tail gut involves the appearance of large intercellular junctions among tail cord cells, and rearrangement of these cells around a newly formed lumen. Mesenchymal characteristics of these cells are gradually lost, and they simultaneously acquire the morphology of epithelial cells. Some cells of the tail cord, located ventral to the tail gut, do not participate in the tail gut formation and form a separate mass of cells without any definitive morphogenetic fate. This surplus group of cells is first evident in 12-day embryos, and it increases in mass during the following 3 days. In 15-day embryos, after the tail gut has completely disappeared, the surplus cells represent all that remains of the tail cord. The mesenchymal-epithelial transformation of the tail cord cells into the cells of the tail gut, and the appearance of the surplus cells, could be considered as the main morphological arguments for the secondary formation of the tail gut.

Animals↗

PubMed1997

Temporally-regulated retinoic acid depletion produces specific neural crest, ocular and nervous system defects.

Both retinoid receptor null mutants and classic nutritional deficiency studies have demonstrated that retinoids are essential for the normal development of diverse embryonic structures (e.g. eye, heart, nervous system, urogenital tract). Detailed analysis of retinoid-modulated events is hampered by several limitations of these models, including that deficiency or null mutation is present throughout gestation, making it difficult to isolate primary effects, and preventing analysis beyond embryolethality. We developed a mammalian model in which retinoid-dependent events are documented during distinct targeted windows of embryogenesis. This was accomplished through the production of vitamin A-depleted (VAD) female rats maintained on sufficient oral retinoic acid (RA) for growth and fertility. After mating to normal males, these RA-sufficient/VAD females were given oral RA doses which allowed for gestation in an RA-sufficient state; embryogenesis proceeded normally until retinoids were withdrawn dietarily to produce a sudden, acute retinoid deficiency during a selected gestational window. In this trial, final RA doses were administered on E11.5, vehicle at E12.5, and embryos analyzed on E13.5; during this 48 hour window, the last RA dose was metabolized and embryos progressed in a retinoid-deficient state. RA-sufficient embryos were normal. Retinoid-depleted embryos exhibited specific malformations of the face, neural crest, eyes, heart, and nervous system. Some defects were phenocopies of those seen in null mutant mice for RXR alpha(-/-), RXR alpha(-/-)/RAR alpha(-/-), and RAR alpha(-/-)/RAR gamma(-/-), confirming that RA transactivation of its nuclear receptors is essential for normal embryogenesis. Other defects were unique to this deficiency model, showing that complete ligand 'knock-out' is required to see those retinoid-dependent events previously concealed by receptor functional redundancy, and reinforcing that retinoid receptors have separate yet overlapping contributions in the embryo. This model allows for precise targeting of retinoid form and deficiency to specific developmental windows, and will facilitate studies of distinct temporal events.

Abnormalities, Multiple↗

PubMed1980

Anatomical analysis of the developmental effects of aneuploidy in man: the Down syndrome.

Detailed anatomical dissections of five Down syndrome (DS) bodies revealed a unique and consistent "internal phenotype" composed of: 1) variations in muscles, 2) peripheral artery variations, and 3) the presence of dilatations and nerve rootlets associated with the spinal accessory and first cervical nerves. Most of these variations may occur occasionally in the normal population, but their more frequent occurrence in the five DS cases provides further support for Shapiro's (1975) hypothesis that one effect of the extra autosome is to increase the instability of normal developmental processes. Three of the variations: 1) the presence of an extra facial muscle, 2) multiple vertebral arteries, and 3) the presence of dilatations and nerve rootlets associated with the spinal accessory and 1st cervical nerves, may be the result of a failure of regression of otherwise transient embryonic structures. A variation of the midfacial muscles of expression, explained as an arrest in development, has not been described previously and, to date, remains a manifestation unique to the trisomy 21 phenotype. Aside from their use in developmental speculation, the sum of these variations may be useful for corroborating diagnoses of suspected post-mortem cases of the DS without cytogenetic confirmation.

Adult↗

PubMed1994

Three-dimensional reconstructions of the primary palate region in normal human embryos.

Our knowledge of the precise spatial relationships of human primary palate morphogenesis remains poorly defined. This is due to intrinsic difficulties that exist in the study of the subject matter and a lack of adequate methodologies. We present a novel new method to allow precise three-dimensional (3-D) visualization of developing embryonic structures in previously sectioned embryos. In our study we focus on human primary palate development. Five normal human embryos from the Carnegie collection were used. 3-D reconstructions appear similar to scanning electron micrographs (SEM); however, unlike in SEM studies, the original specimen has been previously sectioned histologically. 3-D reconstruction from serial sections involved 1) histological preparation of specimen, 2) projection onto digitizing board, 3) digitization, 4) automated reassembly, and 5) relay to interactive optical disc recorder. Detailed observations of each reconstruction were then made. Data generated in this manner may also be used in the near future for quantitative morphometrics. Thus, 3-D reconstruction techniques presented in this paper generated precise spatial information on the development of the human primary palate.

Cleft Lip↗

PubMed2003

Ontogeny of the nasopalatine duct in primates.

Ecological explanations have been put forward to account for the precocious or delayed development of patency in ducts leading to the vomeronasal organ (VNO) in certain mammals. Perinatal function may be related, in part, to the patency or fusion of the vomeronasal and nasopalatine (NPD) ducts. However, few studies have focused on NPD development in primates, which generally have a prolonged period of dependence during infancy. In this study we examined 24 prenatal primates and 13 neonatal primates, and a comparative sample of fetal mice and insectivores. In embryonic and early fetal Microcebus murinus, the NPD was completely fused, whereas in fetuses of later stages the duct was partially fused or completely patent. M. myoxinus of all stages demonstrated some degree of NPD fusion. In all other prenatal primates, the NPD was fused to some extent. Four prenatal insectivores (Tenrec ecaudatus) showed some degree of NPD fusion. In Mus musculus at 19 days gestation, the NPD was patent, although the anatomically separate VNO duct was fused. T. ecaudatus and most of the neonatal primates revealed complete NPD patency. An exception was Saguinus geoffroyi, which exhibited fusion of the NPD near the VNO opening. These observations may relate to differences in perinatal VNO function. The differences noted in our study suggest that M. murinus and M. myoxinus may differ in perinatal VNO functionality and perhaps in related behavior. Observations of neonatal primates suggest that NPD patency may be relatively common at birth and could serve other purposes in addition to being an access route for VNO stimuli.

Animals↗

PubMed2003

Timetable for intestinal rotation in staged human embryos and fetuses.

BACKGROUND: The existing data on intestinal rotation during human development are contradictory regarding the timing of major events, and as such an exact timetable for rotation of the intestine in humans is not yet available. METHODS: We studied the initial formation and rotation of the intestine by microdissection and histological observations in 72 human embryos and fetuses at two to 12 weeks postfertilization. The embryos were classified according to the Carnegie staging system. RESULTS: The primordium of the primitive gut was first observed as a yolk sac at stage 5. With the formation of the embryonic foldings, three divisions of the primitive gut (the foregut, midgut, and hindgut) were observed at stage 10. At stage 12, the primitive gut was located on the midline. At stage 15, a 90 degrees counterclockwise rotation of the intestine began. At stage 16, herniation of the intestine into the umbilical cord was not evident in observations of the external form or a transversely sectioned embryo, but was evident in a sagittally sectioned embryo. There was another 90 degrees counterclockwise rotation at stage 20. Reduction of the intestine was a rapid process, since it was still in the cord in fetuses of <40 mm crown-rump length (CRL), and was reduced above 40 mm in general during nine weeks of development. When the intestine returned to the abdominal cavity, the cecum was located in the right lower quadrant (the adult position). CONCLUSIONS: We have developed a standard timetable to describe the rotation of the intestine. The current results will be helpful in studies describing the pathogenesis of some developmental abnormalities in the intestine due to abnormal rotation.

Embryo, Mammalian↗

PubMed1990

The expression and posttranslational modification of a neuron-specific beta-tubulin isotype during chick embryogenesis.

Five beta-tubulin isotypes are expressed differentially during chicken brain development. One of these isotypes is encoded by the gene c beta 4 and has been assigned to an isotypic family designated as Class III (beta III). In the nervous system of higher vertebrates, beta III is synthesized exclusively by neurons. A beta III-specific monoclonal antibody was used to determine when during chick embryogenesis c beta 4 is expressed, the cellular localization of beta III, and the number of charge variants (isoforms) into which beta III can be resolved by isoelectric focusing. On Western blots, beta III is first detectable at stages 12-13. Thereafter, the relative abundance of beta III in brain increases steadily, apparently in conjunction with the rate of neural differentiation. The isotype was not detectable in non-neural tissue extracts from older embryos (days 10-14) and hatchlings. Western blots of protein separated by two-dimensional gel electrophoresis (2D-PAGE) reveal that the number of beta III isoforms increases from one to three during neural development. This evidence indicates that beta III is a substrate for developmentally regulated, multiple-site posttranslational modification. Immunocytochemical studies reveal that while c beta 4 expression is restricted predominantly to the nervous system, it is transiently expressed in some embryonic structures. More importantly, in the nervous system, immunoreactive cells were located primarily in the non-proliferative marginal zone of the neural epithelia. Regions containing primarily mitotic neuroblasts were virtually unstained. This localization pattern indicates that c beta 4 expression occurs either during or immediately following terminal mitosis, and suggests that beta III may have a unique role during early neuronal differentiation and neurite outgrowth.

Animals↗

PubMed2003

Dlx-1 and Dlx-2 expression in the adult mouse brain: relationship to dopaminergic phenotypic regulation.

Expression of the homeodomain-containing transcription factors Dlx-1 and Dlx-2 in the lateral (LGE) and medial (MGE) ganglionic eminences, subpallial embryonic structures, is required for generation of telencephalic interneurons. LGE- and MGE-derived progenitors migrate and populate a number of forebrain structures, including the cortex, hippocampus, and olfactory bulb (OB). Previous reports focusing on embryogenesis of telencephalic neurons in Dlx-1 and Dlx-2 null mice suggested a specific role for these genes in expression of the OB dopamine (DA) phenotype. We have investigated whether these genes also are expressed in adult brain, especially in those pallial derivatives, such as the OB, hippocampus, and possibly cortex, where neurogenesis continues in adults. With a highly sensitive, nonradioactive in situ hybridization technique and both DLX-2 and pan DLX antisera, widespread expression of both genes was found in adult mouse fore- but not mid- or hindbrain. The adult unilateral naris closure paradigm was employed to establish a causative role for Dlx in regulating tyrosine hydroxylase (TH) expression; TH is the first enzyme in DA biosynthesis. TH mRNA, but not Dlx expression, was significantly down-regulated in the OB ipsilateral to closure. These findings suggest that Dlx-1 and -2 do not play a direct role in DA phenotypic differentiation and TH gene regulation in adult OB. The widespread expression of Dlx mRNA and protein in the adult brain suggests that these genes may have additional roles in mature animals.

Animals↗

PubMed2001

Isolation and expression analysis of three zebrafish angiopoietin genes.

The Tie1 and Tie2 receptor tyrosine kinases and the Tie2 ligands, the angiopoietins, play critical roles in vertebrate vascular embryogenesis, helping to mediate the interaction between endothelial cells and the pericytes or vascular smooth muscle cells that envelop and support them. We have obtained full-length cDNA sequences for zebrafish orthologs of angiopoietin-1 (ang1), angiopoietin-2 (ang2), and angiopoietin-like-3 (angptl3). Ang1 is expressed in head ventral mesenchyme, in the ventromedial region of somites, in mesenchyme surrounding trunk axial vessels, and in the hypochord, a transient embryonic structure of endodermal origin that has been implicated in dorsal aorta assembly in both zebrafish and Xenopus. Ang2 is expressed in head and anterior trunk ventral mesenchyme and the developing pronephric glomeruli. Angptl3 is expressed in the yolk syncytial layer.

Amino Acid Sequence↗

PubMed2006

Targeted gene expression in the zebrafish prechordal plate.

Targeted gene expression is a powerful tool for understanding gene function in vivo. In zebrafish, overexpression of gene products is typically accomplished ubiquitously, without temporal and spatial specificity. However, the yeast Gal4/UAS system can be used for targeted gene expression in zebrafish. Here we describe the generation and characterization of Tg[gsc: Gal4-VP16] transgenic zebrafish lines that harbor a construct encoding Gal4-VP16 transcriptional activator under the control of a fragment of the goosecoid gene promoter. Tg[gsc:Gal4-VP16] embryos express Gal4-VP16 RNA in presumptive prechordal plate mesendoderm during late blastula and throughout gastrulation. By crossing these fish to Tg[UAS-GFP] transgenic fish, we show that the gsc:Gal4-VP16 transgene is capable of driving strong expression of a target gene in the prechordal plate and its derivatives during gastrulation and segmentation. Thus, the use of Tg[gsc:Gal4-VP16] fish can help in understanding gene function in the prechordal plate, an embryonic structure that is crucial for normal neural patterning.

Animals↗