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PubMed1989

Solitary aortic arch artery. A result of surgical ablation of cardiac neural crest and nodose placode in the avian embryo.

Cells from the cardiac neural crest are essential for the normal development of both the heart and the great vessels. If cardiac neural crest is ablated surgically from Hamburger-Hamilton stage 9 chicken embryos, they will develop anomalies of both the heart and great vessels that are similar to anomalies that occur in humans. In the absence of cardiac neural crest, another area of neural ectoderm (nodose placode) provides replacement cells that are less competent than those of the neural crest. In this study, both the cardiac neural crest and the nodose placodes have been surgically ablated. A syndrome of unusual prevalence (47%) and severity was found among the survivors of this surgery, which was characterized by a large undivided aorta that arched dorsally without right or left deviation to become the dorsal aorta. There was no other tributary to the formation of the dorsal aorta. There were no ducti arteriosi, and the pulmonary arteries were both ectopic and hypoplastic. The brachiocephalic arteries were asymmetric and hypoplastic. The association of the aorta with the anlagen of the thyroid and thymus glands, as well as with the inferior ganglion of the vagus nerve, indicated that the solitary surviving aortic arch artery is that of arch III in this syndrome. These results establish a biological limit of the plasticity of the neural ectoderm and give a probable cellular basis for a lethal congenital septal defect.

Animals↗
PubMed2003

A skin defect.

Explore the source record for details and available documents.

Ectodermal Dysplasia↗
PubMed1999

[Trichothiodystrophy: progresssive manifestations].

INTRODUCTION: Trichothiodystrophy is an autosomal recessive genodermatosis associating congenital dysplasia of the hair and neuroectodermal defects. Clinical expression is variable, although abnormalities are generally noted from birth. We report trichothiodystrophy in two brothers with the same phenotype who presented unusual progressive manifestations. OBSERVATIONS: Case 1: A six-year-old boy was seen for vesicular blisters due to photosensitization. Clinical examination showed dry, brittle, unmanageable hair, discrete koilonychia-type nail defects and an ichthyosiform state. The teeth were normal. In addition to psychomotor retardation, the patient presented a dysmorphic syndrome (poorly rimmed low-set ears; thick, triangular upper lip; scaphocephalic skull; short hands) and congenital bilateral cataract. The diagnosis of trichothiodystrophy was confirmed by a study of DNA repair after exposure to ultraviolet light. A repair defect was found similar to that in xeroderma pigmentosum group D. The patient experienced a worsening of psychomotor retardation and episodes of hair loss with edema and inflammation of the scalp resulting from infections. He also showed marked asthenia which resolved spontaneously within a few months. Case 2: The other brother, born as a collodion baby, presented the same clinical picture (cutaneous, exoskeletal, dysmorphic), including congenital bilateral cataract, photosensitivity and a parenchymatous blister-type pulmonary lesion probably secondary to bronchiectasis. The patient's cutaneous state progressively improved. He was seen at six years of age for an episode of inflammatory edema of the scalp with hair loss. Within six months, all of the hair redrew. The diagnosis of trichothiodystrophy was confirmed by a DNA repair defect after exposure to ultraviolet light. DISCUSSION: Trichothiodystrophy is clinically associated with photosensitivity (P), ichthyosis (I), dry, brittle hair (B), intellectual impairment (I), decreased fertility (D) and short stature (S), which accounts for the acronym PIBIDS or IBIDS syndrome, depending on whether photosensitivity is involved or not (actually in about 50 p. 100 of cases). Other possibly associated features include ungueal dysplasias, bilateral cataract, defective teeth, dysmorphic disorders predominant in the ears, neurologic disorders, pulmonary bronchiectasis and recurrent infections. The two cases presented here were thus very symptomatologically complete. The two problems of current concern are psychomotor retardation and temporary hair loss as a result of infections. The latter has only been described once in the literature. This case was similar to ours since photosensitivity was involved. Analysis of DNA repair also showed a defect after exposure to ultraviolet light similar to that found in xeroderma pigmentosum group D. Thus, episodic hair loss could be a symptom characteristic of forms of trichothiodystrophy with a DNA repair defect. However, the explanation for this hair loss is not known. Other ectodermal dysplasias can be complicated by hair loss with superinfection, such as AEC syndrome (ankyloblepharon, ectodermal dysplasia, cleft palate).

Abnormalities, Multiple↗
PubMed2002

Targeted disruption of fibroblast growth factor receptor-1 blocks maturation of visceral endoderm and cavitation in mouse embryoid bodies.

The cellular response to fibroblast growth factors (FGFs) is mediated by receptor tyrosine kinases (FGFR-1 - 4) whose patterns of expression are spatially and temporally restricted during embryogenesis. These receptors have differential ligand binding capacities and are coupled to diverse signalling pathways. In the present study, we have characterized the ability of FGFR-1-deficient mouse embryonic stem (ES) cells to bind FGF-2 and to proliferate in the absence or presence of exogenous FGF-2. Under the same conditions, we also analysed the differentiation of FGFR-1-deficient ES cells into three dimensional, post-implantation, embryonic tissues, known as embryoid bodies (EBs). We show that the targeted disruption of FGFR-1 leads to a reduced binding of FGF-2 which has no significant effect on the proliferation of undifferentiated ES cells. In addition, lack of functional FGFR-1 in differentiating EBs leads to a reduced expression of the endoderm marker gene alpha-fetoprotein (AFP). This deregulation of the AFP gene correlates with defects in the formation of the visceral endoderm, proper differentiation of the ectoderm and thus the organization of the columnar epithelium, and a block of cavitation. Although the addition of exogenous FGF-2 further reduced the expression of AFPmRNA in differentiating mutant EBs, corresponding morphological changes were not observed. Our results indicate that FGFR-1 may play a vital role in endoderm formation.

Animals↗
PubMed1999

Cusp patterning defect in Tabby mouse teeth and its partial rescue by FGF.

Tabby is a mouse mutant characterized by deficient development of the ectodermal organs: teeth, hair, and a subset of glands. Ectodysplasin, the protein encoded by the Tabby gene, was recently identified as a novel TNF-like transmembrane protein but little is known about its function. We have examined the Tabby tooth phenotype in detail by analysis of the adult and embryonic teeth. Tabby first molars had an obvious defect in cusp patterning as the number of cusps was reduced and the buccal and lingual cusps were joined. The disturbance in development was first visible morphologically in the bud stage molar. The primary enamel knot in a cap stage Tabby tooth expressed all enamel knot markers analyzed but was smaller than wild type and the first pair of developing secondary enamel knots was fused. We propose that the Tabby tooth phenotype is due to growth retardation during early stages of development which leads to reduced signaling from the primary enamel knot, followed by deficient growth of the dental epithelium and lack of formation of the last developing secondary enamel knots. The ectodysplasin transcripts were expressed in the outer enamel epithelium and dental lamina. When cultured in vitro Tabby bud/cap stage molars formed fewer cusps than wild-type controls. This phenotype was not rescued by exogenously added EGF despite the previously proposed link between Tabby and EGF. Instead FGF-10 partially restored morphogenesis and stimulated the development of additional tooth cusps in cultured Tabby molars.

Animals↗
PubMed1985

[Clinical and roentgenological study of the hands in synbrachydactyly, constriction band syndrome and cleft hand complex].

One hundred and six cases of synbrachydactyly, 63 cases of constriction band syndrome and 69 cases of cleft hand complex were clinically and roentgenologically studied and the following results were obtained. Synbrachydactyly is a group of hand anomalies in which the bone reduction appears transversely, and its severest form is a hand missing all the hand bones and the distal portion of the forearm, and with rudimentary digits on the stump. The association of dermal syndactyly or pectoralis muscle defect frequently seen in the milder cases of synbrachydactyly would be a secondary change to mesodermal hypoplasia or a related, but isolated malformation. Cleft hand complex which includes ordinary cleft hand, central ray polydactyly and central ray osseous syndactyly is a group of hand anomalies basically due to an ectodermal abnormality of separation of the digits. However, it is frequently associated with mesodermal hypoplasia or defect of various severity. The hand malformation in constriction band syndrome has a definite characteristic that the area of bone reduction is limited in phalanges.

Female↗
PubMed2002

Lefty antagonism of Squint is essential for normal gastrulation.

Activities of a variety of signaling proteins that regulate embryogenesis are limited by endogenous antagonists. The zebrafish Nodal-related ligands, Squint and Cyclops, and their antagonists, Lefty1 and Lefty2, belong to the TGFbeta-related protein superfamily, whose members have widespread biological activities. Among other activities, Nodals direct the formation of most mesendoderm. By inducing their own transcription and that of the Lefties, Nodal signals establish positive and negative autoregulatory loops. To investigate how these autoregulatory pathways regulate development, we depleted zebrafish embryos of Lefty1 and/or Lefty2 by using antisense morpholino oligonucleotides. Loss of Lefty1 causes aberrations during somitogenesis stages, including left-right patterning defects, whereas Lefty2 depletion has no obvious consequences. Depletion of both Lefty1 and Lefty2, by contrast, causes unchecked Nodal signaling, expansion of mesendoderm, and loss of ectoderm. The expansion of mesendoderm correlates with an extended period of rapid cellular internalization and a failure of deep-cell epiboly. The gastrulation defects of embryos depleted of Lefty1 and Lefty2 result from the deregulation of Squint signaling. In contrast, deregulation of Cyclops does not affect morphology or the transcription of Nodal target genes during gastrulation. Furthermore, we find that Cyclops is specifically required for the maintenance of lefty1 and lefty2 transcription.

Animals↗
PubMed2005

Genetic locus half baked is necessary for morphogenesis of the ectoderm.

The zebrafish epiboly mutants partially block epiboly, the vegetalward movement of the blastoderm around the giant yolk cell. Here, we show that the epiboly mutations are located near the centromere of Linkage Group 7 in a single locus, termed the half baked locus. Nevertheless, except for the similar mutants lawine and avalanche, we find the epiboly traits of each of the alleles to be distinguishable, forming an allelic series. Using in situ analysis, we show that the specification and the formation of the germ layers is unaffected. However, during early gastrulation, convergence movements are slowed in homozygous and zygotic maternal dominant (ZMD) heterozygous mutants, especially in the epiblast layer of the blastoderm. Using triple-mutant analysis with squint and cyclops, we show that ablating involution and hypoblast formation in hab has no effect on the epiboly phenotype on the ventral and lateral sides of the embryo, suggesting that the hypoblast has no role in epiboly. Moreover, the triple mutant enhances the depletion of cells on the dorsal side of the embryo, consistent with the idea that convergence movements are defective. Double-mutant analysis with one-eyed pinhead reveals that hab is necessary in the ectodermal portion of the hatching gland. In ZMD heterozygotes, in addition to the slowing of epiboly, morphogenesis of the neural tube is abnormal, with gaps forming in the midline during segmentation stages; later, ectopic rows of neurons form in the widened spinal cord and hindbrain. Cell transplantation reveals that half baked acts both autonomously and nonautonomously in interactions among cells of the forming neural tube. Together, these results suggest that half baked is necessary within the epiblast for morphogenesis during both epiboly and neurulation and suggest that the mechanisms that drive epiboly possess common elements with those that underlie convergence and extension.

Alleles↗
PubMed2003

Carbon monoxide-induced axial skeletal dysmorphogenesis in the chick embryo.

BACKGROUND: Congenital axial skeletal defects affect two to three individuals per 1,000 live births. Without strong evidence for heritability, the cause is assumed to be multi-factorial. Carbon monoxide (CO), an increasingly prevalent environmental toxicant, is a potential environmental component in the etiology of these defects. The chick embryo is a useful model for the characterization and assessment of the mechanism(s) of action of basic developmental mechanisms. METHODS: We have determined a critical period and dose for CO teratogenicity and established a model of CO-induced axial skeletal dysmorphogenesis in the chick embryo. The resulting phenotypes reveal a spectrum of axial skeletal defects ranging from minor defects of the vertebral canal and inter-vertebral discs, to thoraco-lumbar scoliosis, to a tailless phenotype reminiscent of caudal dysgenesis syndrome. These axial skeletal defects have been related to earlier developmental defects in somitogenesis, including errors in segmentation and epithehalization and the expression of the somitic epithelialization factor, Paraxis. We have examined patterns of cell death and apoptosis in CO exposed chick embryos to assess the target tissue(s) involved in the teratogenicity of CO. RESULTS: With respect to the embryonic axis, the neural tube was found to be the most sensitive to CO-induced apoptosis, followed by the somitic mesoderm and Hensen's node. CONCLUSIONS: We hypothesize that the somitic defects and the resulting axial skeletal dysmorphogenesis are caused by disrupted neural tube or ectoderm functions related to somite formation and maintenance. We also hypothesize that CO-induced dysmorphogenesis at this critical period of somitogenesis is caused by the overabundance of CO acting endogenously as a cellular signal, while coincidentally exerting its influence as a toxicant of oxygen delivery or utilization.

Abnormalities, Drug-Induced↗
PubMed2000

CHE-14, a protein with a sterol-sensing domain, is required for apical sorting in C. elegans ectodermal epithelial cells.

BACKGROUND: Polarised trafficking of proteins is critical for normal expression of the epithelial phenotype, but its genetic control is not understood. The regulatory gene lin-26 is essential for normal epithelial differentiation in the nematode Caenorhabditis elegans. To identify potential effectors of lin-26, we characterised mutations that result in lin-26-like phenotypes. Here, we report the phenotypic and molecular analysis of one such mutant line, che-14. RESULTS: Mutations in che-14 resulted in several partially penetrant phenotypes affecting the function of most epithelial or epithelial-like cells of the ectoderm, including the hypodermis, excretory canal, vulva, rectum and several support cells. The defects were generally linked to the accumulation of vesicles or amorphous material near the apical surface, suggesting that secretion was defective. The CHE-14 protein showed similarity to proteins containing sterol-sensing domains, including Dispatched, Patched and NPC1. A fusion protein between full-length CHE-14 and the green fluorescent protein became localised to the apical surface of epithelial cells that require che-14 function. Deletions that removed the predicted transmembrane domains or extracellular loops of CHE-14 abolished apical localisation and function of the protein. CONCLUSIONS: We propose that CHE-14 is involved in a novel secretory pathway dedicated to the exocytosis of lipid-modified proteins at the apical surface of certain epithelial cells. Our data raise the possibility that the primordial function of proteins containing a sterol-sensing domain is to control vesicle trafficking: CHE-14 and Dispatched in exocytosis, Patched and NPC1 in endocytosis.

Amino Acid Motifs↗
PubMed1997

Changes in cell adhesion and extracellular matrix molecules in spontaneous spinal neural tube defects in avian embryos.

Quail embryos (embryonic days 2-2.5) with spontaneous neural tube defects (NTDs), along with age-matched normal embryos, were examined immunocytochemically for the extracellular matrix (ECM) molecules laminin, fibronectin, and chondroitin sulfate proteoglycan, the cell adhesion molecules (CAMs) E- and N-cadherin and neural CAM (NCAM), and the neural crest marker HNK-1. The embryos with NTDs were at the lower limit of the normal stage range and the affected region was about 25% shorter than in normal embryos. Open NTDs occurred in cervical and upper thoracic level, although often the ventral neural tube was morphologically normal. Widened, irregular but closed neural tubes (lower thoracic to sacral levels) showed disorganized mesenchyme-like cells centrally and often multiple lumens. Finger-like tabs projecting from the ectoderm over the neural tube also occurred at lower thoracic to sacral levels. In open NTDs, the E-cadherin-labeled epidermis was incomplete dorsally, and was continuous with the N-cadherin-labeled neural tissue, with a sharp demarcation between E- and N-cadherin-expressing regions, as in the early stages of normal primary neurulation. A sharp inverted peak of epidermis extended ventrally, closely applied to the side of the neural tissue. The intervening matrix labeled less intensely for chondroitin sulfate proteoglycan relative to laminin and fibronectin, in comparison to control embryos. In closed NTDs, the dorsal superficial cell layer (i.e., positionally epidermis) was not separated from the underlying neural tissue by a band of matrix as in control embryos. In addition, this layer expressed E-cadherin (as in normal embryos), but coexpressed N-cadherin and NCAM, which are not normally found here at this stage. This overlap region resembled the mid-dorsal tissue at earlier stages in normal secondary neurulation in the tail-bud. The tabs of tissue appeared to be localized hypertrophy of the epidermal and neural ectoderm, and also showed codistribution of E- and N-cadherin. In all these defects, matrix molecules occurred within (rather than around) the neural and epidermal epithelia. HNK-1-labeled neural crest cells were frequently absent in regions of NTDs, in contrast to control embryos. These results show that matrix and cell adhesion molecules are disturbed in spontaneous NTDs at the time of neurulation, and therefore could be involved in the generation of the defects by altering cell adhesion-dependent morphogenetic events.

Animals↗
PubMed2003

Alterations in desmosome size and number coincide with the loss of keratinocyte cohesion in skin with homozygous and heterozygous defects in the desmosomal protein plakophilin 1.

Recessive mutations in the desmosomal plaque protein plakophilin 1 (PkP1) underlie ectodermal dysplasia/skin fragility syndrome (MIM 604536). We undertook an immunohistochemical and quantitative electron microscopic examination of suprabasal desmosomes from 4 skin samples from 3 PkP1 deficient patients, an unaffected carrier with a PKP1 heterozygous acceptor splice site mutation and 5 healthy control subjects. Desmosomal plaque size (>50 desmosomes per individual) and frequency (>20 high power fields, HPF) were assessed. Compared with controls, desmosomes were reduced dramatically both in size (49%) and frequency (61%) in the lower suprabasal layers (LSB) in PkP1 null patients (P<0.01). In the LSB compartment of the heterozygous carrier, corresponding reductions were 37% and 20%, respectively (P<0.01). Surprisingly, the PkP1 null patient's upper suprabasal layer, (USB), desmosome size was larger (59%, P<0.01) than the control value, and showed increased desmoglein 1 and PkP2 USB staining. The USB desmosome frequency in PKP1 null patients was similar to the LSB compartment (but reduced by 43% compared to USB controls). The carrier showed no difference in the USB desmosome size and frequency compared with the controls (P>0.05). The PKP1 null patients showed poorly developed inner and outer desmosomal plaques. Thus, both the patients and unaffected carrier showed reductions in the LSB desmosome size and number; despite only PkP1 null patients exhibiting any phenotype. These findings attest to the molecular recruiting and stabilizing roles of PkP1 in desmosome formation, particularly in the LSB compartment.

Adolescent↗
PubMed2003

Towards a new classification of ectodermal dysplasias.

Ectodermal dysplasias (EDs) constitute a large and complex group of diseases characterized by various defects in hair, nails, teeth and sweat glands. Of the 170 EDs described so far, fewer than 30 have been explained at the molecular level with identification of the causative gene. This review proposes a new classification of EDs based on the function of the protein encoded by the mutated gene. The EDs are reviewed in light of the recent molecular and biochemical findings and an attempt is made to classify ED causative genes into four major functional subgroups: cell-cell communication and signalling; adhesion; transcription regulation; and development.

Cell Adhesion↗
PubMed1990

Structural hair abnormalities in ectodermal dysplasia.

The hair of patients with three ectodermal dysplasias--ectrodactyly ectodermal dysplasia clefting syndrome (EEC); orofacial-digital syndrome (OFD) type I; and anhidrotic ectodermal dysplasia syndrome (AED)--were studied by scanning electron microscopy. While no pathognomonic abnormalities were noted for each condition, hair shaft structural defects were evident in all patients studied. The EEC clefting syndrome and OFD I shared the most deforming defects, while AED had fewer.

Abnormalities, Multiple↗
PubMed1999

p63 is essential for regenerative proliferation in limb, craniofacial and epithelial development.

The p63 gene, a homologue of the tumour-suppressor p53, is highly expressed in the basal or progenitor layers of many epithelial tissues. Here we report that mice homozygous for a disrupted p63 gene have major defects in their limb, craniofacial and epithelial development. p63 is expressed in the ectodermal surfaces of the limb buds, branchial arches and epidermal appendages, which are all sites of reciprocal signalling that direct morphogenetic patterning of the underlying mesoderm. The limb truncations are due to a failure to maintain the apical ectodermal ridge, a stratified epithelium, essential for limb development. The embryonic epidermis of p63-/- mice undergoes an unusual process of non-regenerative differentiation, culminating in a striking absence of all squamous epithelia and their derivatives, including mammary, lacrymal and salivary glands. Taken together, our results indicate that p63 is critical for maintaining the progenitor-cell populations that are necessary to sustain epithelial development and morphogenesis.

Animals↗
PubMed1993

Pili trianguli et canaliculi: a distinctive hair shaft defect leading to uncombable hair.

Uncombable hair syndrome refers to a clinical disorder characterized by scalp hairs arranged in bundles in all directions that resist to brush and comb. Several entities may lead to spun-glass hair. As a rule the syndrome becomes obvious during the first years of life. The hair is normal in quantity, and increased fragility is not a common feature. The hair is often dry with silvery blond color. Under the light microscope the hairs may appear normal. Scanning electron microscopy shows a characteristic triangular, kidney- or heat-shaped diameter with typical longitudinal canalicular deformation. We present a 9-year-old girl with the typical clinical features of pili trianguli et canaliculi. Investigation by scanning electron microscopy confirmed the diagnosis. In addition the girl had enamel defects of the teeth and nail abnormalities that classify for a subtype of ectodermal dysplasia.

Child↗
PubMed2004

The zinc finger mutation C417R of I-kappa B kinase gamma impairs lipopolysaccharide- and TNF-mediated NF-kappa B activation through inhibiting phosphorylation of the I-kappa B kinase beta activation loop.

The activation of the I-kappaB kinase (IKK) complex by TNF or LPS stimulates phosphorylation and degradation of I-kappaBalpha, leading to the nuclear translocation of NF-kappaB. The IKK complex is mainly composed of two catalytic subunits, IKKalpha and IKKbeta, and a chaperon subunit IKKgamma. Although IKKgamma does not have catalytic activity, it is essential for IKK activation induced by multiple stimuli. Importantly, the key residue cysteine 417 at the zinc finger domain of IKKgamma has been found to be mutated to arginine (IKKgammaC417R) in a human genetic disorder called the anhydrotic ectodermal dysplasia with immunodeficiency. To understand the underlying mechanisms of immunodeficiency, we examined whether the IKKgammaC417R mutant modified IKK activation and NF-kappaB transcription stimulated by LPS or TNF in human monocytes. We found that overexpression of IKKgammaC417R severely impaired LPS- and TNF-induced I-kappaBalpha phosphorylation and degradation in a dominant-negative fashion. Also, LPS- and TNF-induced NF-kappaB transcription was inhibited by IKKgammaC417R. The reconstitution of IKKgamma, but not IKKgammaC417R, in IKKgamma-deficient cells restored NF-kappaB signaling, indicating the zinc finger structure of IKKgamma plays a key role in IKK activation. Moreover, C417R mutation in IKKgamma abolished both LPS- and TNF-induced phosphorylation of the activation loop of IKKbeta. Collectively, our results indicated that the zinc finger structure of IKKgamma plays a key role in LPS- and TNF-induced NF-kappaB activation. The anhydrotic ectodermal dysplasia with immunodeficiency patients' immunodeficiency may be associated with NF-kappaB defect in response to bacterial stimulation.

Active Transport, Cell Nucleus↗