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PubMed1995

Evaluation of candidate genes for familial brachydactyly.

Type A1 brachydactyly in humans is a recognisable syndrome characterised by shortening of the middle phalanx of all digits with occasional fusion of the middle and terminal phalanges. The purpose of this study was to evaluate candidate genes for type A1 brachydactyly in two families with multiple affected members. Several classes of genes have been implicated in the control of distal limb development including homeobox containing genes (MSX1, MSX2) some members of the homeobox gene family, and genes encoding growth factors of the FGF, TGF, and PDGF families. Homeobox (Hox) genes are a family of developmental control genes activated early in embryogenesis that encode positional information along the anterior-posterior body axis and specify distinct spatial domains within developing limbs. Growth factor genes can regulate the proliferation and differentiation of various embryonic structures including limb buds and have been shown to influence Hox gene expression. Candidate genes HOXD, MSX1, MSX2, FGF-1, and FGF-2 were excluded in one family. The brachydactyly type A1 gene or locus was not found in either of the two families studied.

Base Sequence↗

PubMed2003

Generating the cerebral cortical area map.

The view that the cortical primordium is initially patterned in similar ways to the rest of the embryo has been a conceptual breakthrough. We now have a new starting point for understanding how the cortical area map is established and how maps may change and evolve. Here we review findings that signaling molecules secreted from distinct cortical signaling centers establish positional information in the cortical primordium and regulate regional growth. In other embryonic systems, positional signals would regulate the patterned expression of transcription factors, leading, in a gene regulatory cascade, to the patterned differentiation of the tissue. We discuss candidate transcription factors with respect to such a model of cortical patterning. Finally, embryonic structures interact to pattern one another. We review data suggesting that the thalamus and cortex are patterned independently then interact to generate the final cortical area map.

Animals↗

PubMed2006

Regulation of Wolffian duct development.

Wolffian ducts (WDs) are the embryonic structures that form the male internal genitalia. These ducts develop in both the male and female embryo. However, in the female they subsequently regress, whereas in the male they are stabilised by testosterone. The WDs then develop into separate but contiguous organs, the epididymis, vas deferens and seminal vesicles. Recently, considerable progress has been made in identifying genes that are involved in these different stages of development which is described in this review. In addition, WD development in (atypical forms of) cystic fibrosis and intersex disorders, such as the complete androgen insensitivity syndrome, 17beta-hydroxysteroid dehydrogenase deficiency and LH-receptor defects, is discussed. The apparent increase in male reproductive tract disorders is briefly discussed from the perspective of the potential endocrine-disrupting effects of the numerous chemicals in the environment to which the developing male foetus can be exposed.

Androgens↗

PubMed2003

Spatial and temporal patterns of ERK signaling during mouse embryogenesis.

Signaling between tissues is essential to form the complex, three-dimensional organization of an embryo. Because many receptor tyrosine kinases signal through the RAS-MAPK pathway, phosphorylated ERK can be used as an indicator of when and where signaling is active during development. Using whole-mount immunohistochemistry with antibodies specific to phosphorylated ERK1 and ERK2, we analyzed the location, timing, distribution, duration and intensity of ERK signaling during mouse embryogenesis (5-10.5 days postcoitum). Spatial and temporal domains of ERK activation were discrete with well-defined boundaries, indicating specific regulation of signaling in vivo. Prominent, sustained domains of ERK activation were seen in the ectoplacental cone, extra-embryonic ectoderm, limb buds, branchial arches, frontonasal process, forebrain, midbrain-hindbrain boundary, tailbud, foregut and liver. Transient activation was seen in neural crest, peripheral nervous system, nascent blood vessels, and anlagen of the eye, ear and heart. In the contiguous domains of ERK signaling, phospho-ERK staining was cytoplasmic with no sign of nuclear translocation. With few exceptions, the strongest domains of ERK activation correlated with regions of known or suspected fibroblast growth factor (FGF) signaling, and brief incubation with an inhibitor of the fibroblast growth factor receptor (FGFR) specifically diminished the phospho-ERK staining in these regions. Although many domains of ERK activation were FGFR-dependent, not all domains of FGF signaling were phospho-ERK positive. These studies identify key domains of sustained ERK signaling in the intact mouse embryo, give significant insight into the regulation of this signaling in vivo and pinpoint regions where downstream target genes can be sought.

Animals↗

PubMed2004

Six1 promotes a placodal fate within the lateral neurogenic ectoderm by functioning as both a transcriptional activator and repressor.

Cranial placodes, which give rise to sensory organs in the vertebrate head, are important embryonic structures whose development has not been well studied because of their transient nature and paucity of molecular markers. We have used markers of pre-placodal ectoderm (PPE) (six1, eya1) to determine that gradients of both neural inducers and anteroposterior signals are necessary to induce and appropriately position the PPE. Overexpression of six1 expands the PPE at the expense of neural crest and epidermis, whereas knock-down of Six1 results in reduction of the PPE domain and expansion of the neural plate, neural crest and epidermis. Using expression of activator and repressor constructs of six1 or co-expression of wild-type six1 with activating or repressing co-factors (eya1 and groucho, respectively), we demonstrate that Six1 inhibits neural crest and epidermal genes via transcriptional repression and enhances PPE genes via transcriptional activation. Ectopic expression of neural plate, neural crest and epidermal genes in the PPE demonstrates that these factors mutually influence each other to establish the appropriate boundaries between these ectodermal domains.

Animals↗

PubMed2005

Matching catalytic activity to developmental function: tolloid-related processes Sog in order to help specify the posterior crossvein in the Drosophila wing.

The Drosophila tolloid (tld) and tolloid related (tlr) gene products belong to a family of developmentally important proteases that includes Bone Morphogenetic Protein 1 (Bmp1). Tld is required early in Drosophila development for proper patterning of dorsal embryonic structures, whereas Tlr is required later during larval and pupal stages of development. The major function of Tld is to augment the activity of Decapentaplegic (Dpp) and Screw (Scw), two members of the Bmp subgroup of the Tgf beta superfamily, by cleaving the Bmp inhibitor Short gastrulation (Sog). In this study, we provide evidence that Tlr also contributes to Sog processing. Tlr cleaves Sog in vitro in a Bmp-dependent manner at the same three major sites as does Tld. However, Tlr shows different site selection preferences and cleaves Sog with slower kinetics. To test whether these differences are important in vivo, we investigated the role of Tlr and Tld during development of the posterior crossvein (PCV) in the pupal wing. We show that tlr mutants lack the PCV as a result of too little Bmp signaling. This is probably caused by excess Sog activity, as the phenotype can be suppressed by lowering Sog levels. However, Tld cannot substitute for Tlr in the PCV; in fact, misexpressed Tld can cause loss of the PCV. Reducing levels of Sog can also cause loss of the PCV, indicating that Sog has not only an inhibitory but also a positive effect on signaling in the PCV. We propose that the specific catalytic properties of Tlr and Tld have evolved to achieve the proper balance between the inhibitory and positive activities of Sog in the PCV and early embryo, respectively. We further suggest that, as in the embryo, the positive effect of Sog upon Bmp signaling probably stems from its role in a ligand transport process.

Animals↗

PubMed1991

Deep cytoplasmic rearrangements during early development in Xenopus laevis.

The egg of the frog Xenopus is cylindrically symmetrical about its animal-vegetal axis before fertilization. Midway through the first cell cycle, the yolky subcortical cytoplasm rotates 30 degrees relative to the cortex and plasma membrane, usually toward the side of the sperm entry point. Dorsal embryonic structures always develop on the side away from which the cytoplasm moves. Details of the deep cytoplasmic movements associated with the cortical rotation were studied in eggs vitally stained during oogenesis with a yolk platelet-specific fluorescent dye. During the first cell cycle, eggs labelled in this way develop a complicated swirl of cytoplasm in the animal hemisphere. This pattern is most prominent on the side away from which the vegetal yolk moves, and thus correlates in position with the prospective dorsal side of the embryo. Although the pattern is initially most evident near the egg's equator or marginal zone, extensive rearrangements associated with cleavage furrowing (cytoplasmic ingression) relocate portions of the swirl to vegetal blastomeres on the prospective dorsal side.

Animals↗

PubMed1991

Macromere cell fates during sea urchin development.

This paper examines the cell lineage relationships and cell fates in embryos of the sea urchin Strongylocentrotus purpuratus leading to the various cell types derived from the definitive vegetal plate territory or the veg2 tier of cells. These cell types are gut, pigment cells, basal cells and coelomic pouches. They are cell types that constitute embryonic structures through cellular migration or rearrangement unlike the relatively non-motile ectoderm cell types. For this analysis, we use previous knowledge of lineage to assign macromeres to one of four types: VOM, the oral macromere; VAM, the aboral macromere, right and left VLM, the lateral macromeres. Each of the four macromeres contributes progeny to all of the cell types that descend from the definitive vegetal plate. Thus in the gut each macromere contributes to the esophagus, stomach and intestine, and the stripe of labeled cells descendant from a macromere reflects the re-arrangement of cells that occurs during archenteron elongation. Pigment cell contributions exhibit no consistent pattern among the four macromeres, and are haphazardly distributed throughout the ectoderm. Gut and pigment cell contributions are thus radially symmetrical. In contrast, the VOM blastomere contributes to both of the coelomic pouches while the other three macromeres contribute to only one or the other pouch. The total of the macromere contribution amounts to 60% of the cells constituting the coelomic pouches.

Animals↗

PubMed1994

Role of the teashirt gene in Drosophila midgut morphogenesis: secreted proteins mediate the action of homeotic genes.

Homeotic genes control the development of embryonic structure by coordinating the activities of downstream 'target' genes. The identities and functions of target genes must be understood in order to learn how homeotic genes control morphogenesis. Drosophila midgut development is regulated by homeotic genes expressed in the visceral mesoderm, where two of their target genes have been identified. Both encode secreted proteins. The Ultrabithorax (Ubx) homeotic gene activates transcription of the decapentaplegic (dpp) gene, which encodes a TGF beta class protein, while in adjacent mesoderm cells the abdominal-A (abd-A) homeotic gene activates transcription of the wingless (wg) gene, which encodes a Wnt class protein. The homeotic genes Antennapedia (Antp) and Sex combs reduced (Scr) act in more anterior midgut regions. Here we report the identification of another homeotic gene target in the midgut mesoderm, the teashirt (tsh) gene, which encodes a protein with zinc finger motifs. tsh is necessary for proper formation of anterior and central midgut structures. Antp activates tsh in anterior midgut mesoderm. In the central midgut mesoderm Ubx, abd-A, dpp, and wg are required for proper tsh expression. The control of tsh by Ubx and abd-A, and probably also by Antp, is mediated by secreted signaling molecules. By responding to signals as well as localized transcription regulators, the tsh transcription factor is produced in a spatial pattern distinct from any of the homeotic genes.

Animals↗

PubMed1996

In vitro analysis of epiblast tissue potency for hematopoietic cell differentiation.

In murine embryogenesis, all cells that will constitute the embryonic structures originate from the epiblast (primitive ectoderm) tissue, the epithelial cell sheet of the gastrulating embryo. The cells of this tissue are totipotent at the beginning of gastrulation, but at the end of this period are specified to particular cell lineages. Thus, it is likely that during murine gastrulation, the potency of epiblast cells that were originally totipotent becomes restricted as development progresses. However, the mechanisms of this process are unknown. We have investigated this process in vitro, focusing on the hematopoietic cell lineage. To detect the hematogenic potency of the epiblast tissue, we established an in vitro culture system in which the hematopoietic cell differentiation of the epiblast tissue was supported by a stromal cell layer. With this culture system, we investigated the process by which this potency becomes spatially and temporally restricted during gastrulation. The results showed that hematogenic potency resides in the entire epiblast of the early- to mid-gastrulating embryo, but becomes restricted to the posterior half of the epiblast at the headfold stage. Furthermore, we showed that this process is altered by exogenous bone morphogenetic protein-4 (BMP-4) or activin A, which may be mesoderm inducers in Xenopus embryogenesis.

Activins↗

PubMed1996

Mutations affecting cell fates and cellular rearrangements during gastrulation in zebrafish.

One of the major challenges of developmental biology is understanding the inductive and morphogenetic processes that shape the vertebrate embryo. In a large-scale genetic screen for zygotic effect, embryonic lethal mutations in zebrafish we have identified 25 mutations that affect specification of cell fates and/or cellular rearrangements during gastrulation. These mutations define at least 14 complementation groups, four of which correspond to previously identified genes. Phenotypic analysis of the ten novel loci revealed three groups of mutations causing distinct effects on cell fates in the gastrula. One group comprises mutations that lead to deficiencies in dorsal mesodermal fates and affect central nervous system patterning. Mutations from the second group affect formation of ventroposterior embryonic structures. We suggest that mutations in these two groups identify genes necessary for the formation, maintenance or function of the dorsal organizer and the ventral signaling pathway, respectively. Mutations in the third group affect primarily cellular rearrangements during gastrulation and have complex effects on cell fates in the embryo. This group, and to some extent mutations from the first two groups, affect the major morphogenetic processes, epiboly, convergence and extension, and tail morphogenesis. These mutations provide an approach to understanding the genetic control of gastrulation in vertebrates.

Animals↗

PubMed1998

Involvement of the sonic hedgehog, patched 1 and bmp2 genes in patterning of the zebrafish dermal fin rays.

The signaling molecule encoded by Sonic hedgehog (shh) participates in the patterning of several embryonic structures including limbs. During early fin development in zebrafish, a subset of cells in the posterior margin of pectoral fin buds express shh. We have shown that regulation of shh in pectoral fin buds is consistent with a role in mediating the activity of a structure analogous to the zone of polarizing activity (ZPA) (Akimenko and Ekker (1995) Dev. Biol. 170, 243-247). During growth of the bony rays of both paired and unpaired fins, and during fin regeneration, there does not seem to be a region equivalent to the ZPA and one would predict that shh would play a different role, if any, during these processes specific to fish fins. We have examined the expression of shh in the developing fins of 4-week old larvae and in regenerating fins of adults. A subset of cells in the basal layer of the epidermis in close proximity to the newly formed dermal bone structures of the fin rays, the lepidotrichia, express shh, and ptc1 which is thought to encode the receptor of the SHH signal. The expression domain of ptc1 is broader than that of shh and adjacent blastemal cells releasing the dermal bone matrix also express ptc1. Further observations indicate that the bmp2 gene, in addition to being expressed in the same cells of the basal layer of the epidermis as shh, is also expressed in a subset of the ptc1-expressing cells of the blastema. Amputations of caudal fins immediately after the first branching point of the lepidotrichia, and global administration of all-trans-retinoic acid, two procedures known to cause fusion of adjacent rays, result in a transient decrease in the expression of shh, ptc1 and bmp2. The effects of retinoic acid on shh expression occur within minutes after the onset of treatment suggesting direct regulation of shh by retinoic acid. These observations suggest a role for shh, ptc1 and bmp2 in patterning of the dermoskeleton of developing and regenerating teleost fins.

Animals↗

PubMed2001

Neuroendocrine neoplasms of the mediastinum.

Neuroendocrine neoplasms of the mediastinum form part of a family of tumors characterized by genotypic, immunophenotypic, and functional properties of neuroendocrine differentiation. Although rare, these tumors have been the source of much attention and controversy in the literature. Their nomenclature and classification, in particular, have continued to evolve over the years. Such tumors comprise lesions derived from neuroendocrine elements within the thymus, from paraganglionic rests, or from misplaced embryonal structures within the mediastinum. The most common neuroendocrine neoplasms of this anatomic region, however, correspond to neuroendocrine carcinomas of the thymus. The light microscopic, immunohistochemical, and ultrastructural features of these tumors are reviewed along with the advances in our understanding of these lesions and current trends in nomenclature and terminology.

Adult↗

PubMed2001

A new approach to classify cleft lip and palate.

OBJECTIVE: To propose a new method, which allows for a complete description of primary and secondary cleft palates, incorporating elements that are related to the palate, lip, and nose that will also reflect the complexity of this problem. METHOD: To describe the type of cleft, two embryonic structures were considered: (1) the primary palate, formed by the prolabium, premaxilla, and columella and (2) the secondary palate, which begins at the incisive foramen and is formed by a horizontal portion of the maxilla, the horizontal portion of the palatine bones, and the soft palate. Anatomical characteristics to be considered were defined, and a new method is proposed to more fully describe any cleft. RESULTS: A description of five cases was made using the method proposed in this work and compared with other published methods for the classification and description of clefts. CONCLUSIONS: A mathematical expression was developed to characterize clefts of the primary palate, including the magnitude of palatal segment separation and the added complexity of bilateral clefts, yielding a numerical score that reflects overall complexity of the cleft. Clefts of the secondary palate are also considered in a separate score. Using this method, it is possible to incorporate elements that are not considered in other approaches and to describe all possible clefts that may exist.

Algorithms↗

PubMed2005

Glomerular permeability is altered by loss of P0, a myelin protein expressed in glomerular epithelial cells.

The myelin protein 0 (MPZ or P0) is a transmembrane glycoprotein that represents the most abundant myelin component. Mutations in the P0 gene are associated with one form of autosomal dominant demyelinating peripheral neuropathy, Charcot-Marie-Tooth disease type 1B (CMT1B). Because CMT1 may be associated with renal involvement, mostly focal segmental glomerulosclerosis, we hypothesized that P0 could be expressed in the kidney. P0 mRNA was detected by reverse transcriptase-PCR in the human and mouse renal cortex. P0 transcripts were identified by in situ hybridization at different stages of the mouse kidney development, especially in embryonic structures that give rise to the glomerulus. P0 protein was also detected by Western blot in human and rat glomerular extracts and in a human podocyte cell line using a monoclonal anti-P0 antibody. Immunofluorescence studies on human kidney sections showed that the podocytes were intensely labeled. Immunogold electron microscopy disclosed a predominant staining of the membranes of intracellular vesicles in podocytes. P0 was also detected in the podocyte cell membrane, including at the foot processes. P0(-/-) mice exhibited mild growth retardation and demyelinating neuropathy similar to the one observed in patients with CMT1B. They also presented mild albuminuria, without significant ultrastructural change of the glomerular basement membrane or the podocytes. These results demonstrate that P0, the major myelin protein, is also expressed during nephrogenesis and in mature kidney, mostly in podocytes. They suggest that P0 gene mutations might be involved in renal diseases.

Adult↗

PubMedDate not supplied

Optic nerve hypoplasia and colobomatous defects.

The case of a 21-year-old woman with an optic nerve head coloboma and optic pit in one eye, a hypoplastic optic nerve head in the second eye, and a small retinochoroidal coloboma in each eye is presented. The probable etiology is some unknown insult involving several ocular embryonic structures and occurring during the 11-mm to 20-mm stage of development. The occurrence of these multiple anomalies in the same patient lends further support to the theory that optic disc colobomas and optic nerve hypoplasia represent a spectrum of developmental anomalies of the optic nerve.

Abnormalities, Multiple↗

PubMed2000

[The classification of congenital clefts and defects of the palate after uranoplasty. The clinico-embryo-pathogenetic principles].

The authors suggest classifying palatal clefts as an individual nosological entity resultant from impaired differentiation, growth, and fusion of primary embryonal structures forming the palate as an anatomical structure. Definition of the palatal interface on the basis of the embryo-pathogenetic principle underlies the working classification of palatal defects developing after uranoplasty.

Cleft Palate↗

PubMed2002

The beginnings of developmental biology in Swiss universities.

This contribution describes the pioneer work in Developmental Biology, initiated by Swiss scientists. The anatomist W. His (1831-1904) deserves credit as the founder of "Descriptive Embryology". Using novel microscopical techniques, he documented the formation of the embryonic body of various vertebrates as an approach to reveal the mechanisms of morphogenesis. Based on studies of the chick embryo, he designed a fate map of the germ-disk, comprising organ-forming regions, from which the corresponding embryonic structures originate. F. Baltzer (1886-1974) initiated original studies on the role of nuclear and cytoplasmic factors in the development of sea urchin hybrids and newt merogons. Through his experiments on interspecific and intergeneric chimeras of amphibians, he further contributed to the emerging field of "Developmental Genetics". F.E. Lehmann (1901-70) inaugurated work on "Chemical Embryology" and later moved to "Cell Biology". His discoveries on stage- and regional-specific inhibition of morphogenesis by LiCl in newt embryos were important for the understanding of malformations. Further studies regarding the action of cytostatic substances on tail regeneration in tadpoles were intended to yield information on growth control. Original contributions to "Experimental Embryology" were also made by R. Geigy (1902-1995), who devised an ingenuous procedure for obtaining sterile Drosophila flies by UV-irradiation of eggs. In later studies on anuran metamorphosis, he discovered that the morphogenetic effects of the metamorphic hormones are organ-specific and that competence of the larval tissues to respond to thyroid hormone is stage-dependent.

Developmental Biology↗