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A boy with dysplastic features had to be treated for recurrent diarrhoea and bronchitis since his tenth month of life. Defects in humoral and cellular immunity were found. The ecto-mesodermal abnormalities are so characteristic that in connection with the immunological changes it seems to be justified to assume a yet undescribed syndrome.
The molecular basis of X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) has remained elusive. Here we report hypomorphic mutations in the gene IKBKG in 12 males with EDA-ID from 8 kindreds, and 2 patients with a related and hitherto unrecognized syndrome of EDA-ID with osteopetrosis and lymphoedema (OL-EDA-ID). Mutations in the coding region of IKBKG are associated with EDA-ID, and stop codon mutations, with OL-EDA-ID. IKBKG encodes NEMO, the regulatory subunit of the IKK (IkappaB kinase) complex, which is essential for NF-kappaB signaling. Germline loss-of-function mutations in IKBKG are lethal in male fetuses. We show that IKBKG mutations causing OL-EDA-ID and EDA-ID impair but do not abolish NF-kappaB signaling. We also show that the ectodysplasin receptor, DL, triggers NF-kappaB through the NEMO protein, indicating that EDA results from impaired NF-kappaB signaling. Finally, we show that abnormal immunity in OL-EDA-ID patients results from impaired cell responses to lipopolysaccharide, interleukin (IL)-1beta, IL-18, TNFalpha and CD154. We thus report for the first time that impaired but not abolished NF-kappaB signaling in humans results in two related syndromes that associate specific developmental and immunological defects.
This hypothesis is offered by a neurological surgeon interested in anomalies of the central nervous system. It is based on accumulating evidence indicating that some neural tube defects result not from failure of the tube to close but from its rupture after closure. The central nervous system, serving all organs, is the first to develop and its maldevelopment may cause damage to other emerging structures. The neural tube closes during the fourth week and is immediately distended by a proteinaceous neural tube fluid (NTF) secreted by its lining cells at a pressure four to five times that of the surrounding amniotic fluid. This NTF has been miscalled "cerebrospinal fluid." The choroid plexus does not begin to secrete true cerebrospinal fluid (CSF) until 2 weeks later. If oversecretion of NTF should occur during this 2-week interval, the resulting overexpansion of the neural tube may spread apart the developing somite, eventuating in a combination of anterior and posterior spina bifida that constitutes bilateral hemivertebrae. If the distending neural tube ruptures beneath intact cutaneous ectoderm, the escaping NTF will infiltrate mesoderm. The resulting dislocation of cells and their possible injury by the extraneous protein may damage the as yet unidentifiable anlagen of mesodermal organs. If neural tube overdistention splits the underlying notochord and damages primitive gut, anomalies of entodermal organs may result. The neuroenteric cyst is one such anomaly that the neurosurgeon is called upon to treat. He finds it accompanied by hemivertebrae and hydromyelia. A preliminary report on this hypothesis has been published (Gardner and Breuer, '80).
NEMO (NF-kappaB essential modifier)/IKKgamma (IkappaB kinase-gamma) is required for the activation of the IkappaB kinase complex (IKK) by inflammatory stimuli such as tumor necrosis factor (TNF-alpha). Here we show that TNF-alpha stimulates the ubiquitination of NEMO in a manner that does not appear to target it for degradation and that is impaired by mutations in the NEMO zinc finger. Mutations of the zinc finger are found in patients with hypohidrotic ectodermal dysplasia with immunodeficiency (HED-ID) and lead to the impairment of TNF-alpha-stimulated IKK phosphorylation and activation. In addition, the ubiquitination of NEMO is mediated by c-IAP1, an inhibitor of apoptosis protein that is a component of the TNF receptor signaling complex. Thus, the ubiquitination of NEMO mediated by c-IAP1 likely plays an important role in the activation of IKK by TNF-alpha. Also, defective NEMO ubiquitination may be responsible for the impaired cellular NF-kappaB signaling found in patients with HED-ID.
PURPOSE: Hypospadias is a common congenital anomaly that may be treated with surgical reconstruction. In the majority of cases the etiology remains elusive. Although androgens are clearly critical for penile development, defects in androgen metabolism and/or the androgen receptor explain only a small subset of cases of hypospadias. Strategies are presented for understanding the etiology of hypospadias. MATERIALS AND METHODS: Current scientific reports on the etiology of hypospadias were reviewed, and the embryology and possible mechanisms of urethral and penile formation are presented. RESULTS: A new theory of glandular human urethral development via endodermal cellular differentiation is proposed to replace the classic explanation of ectodermal intrusion. CONCLUSIONS: Careful studies of penile and urethral development have led to a better understanding of genital embryology. Future areas of study, such as endocrine disrupters, mesenchymal-epithelial interactions and mechanisms of penile growth, are proposed to explain the etiology of hypospadias.
The recombinant limb is a model system that has proved fruitful for analyzing epithelial-mesenchymal interactions and understanding the functional properties of the components of the limb bud. Here we present an overview of some of the insights obtained through the use of this technique. Among these are the understanding that fore or hind limb identity is inherent to the limb bud mesoderm, that the apical ectodermal ridge (AER) is a permissive signaling center and that the limb bud ectoderm plays a central role in the control of dorsoventral polarity. Recombinant limb studies have also allowed the identification of the affected tissue component in several limb mutants. More recently this model has been applied to the study of regulation of gene expressions related to patterning. In this report we use recombinant limbs to analyze pattering of the Pax3 expressing limb muscle cell lineage in the early stages of limb development. In recombinant limbs made without the zone of polarizing activity (ZPA), myoblasts appear intermingled with other mesodermal cells at the beginning of the recombinant limb development. Rapidly thereafter, the muscle precursors segregate and organize around the central forming chondrogenic core of the recombinant. Although this segregation is reminiscent of that occurring during normal development, the myoblasts in the recombinant fail to proliferate appropriately and also fail to migrate distally. Consequently, the muscle pattern in the recombinant limb is defective indicating that normal patterning cues are absent. However, recombinant limbs polarized with a ZPA exhibited a larger mass of muscle cells and a more normal morphogenesis, supporting a role for this signaling center in limb muscle development. Finally, we have ruled out host somite contributions to recombinant limbs by grafting chick recombinant limbs to quail hosts. This initial report demonstrates the value of the recombinant limb model system for dissecting the environmental cues required for normal muscle limb patterning.
Atrophins are evolutionarily conserved proteins that are thought to act as transcriptional co-repressors. Mammalian genomes contain two atrophin genes. Dominant polyglutamine-expanded alleles of atrophin 1 have been identified as the cause of dentatorubralpallidoluysian atrophy, an adult-onset human neurodegenerative disease with similarity to Huntington's. In a screen for recessive mutations that disrupt patterning of the early mouse embryo, we identified a line named openmind carrying a mutation in atrophin 2. openmind homozygous embryos exhibit a variety of patterning defects that first appear at E8.0. Defects include a specific failure in ventralization of the anterior neural plate, loss of heart looping and irregular partitioning of somites. In mutant embryos, Shh expression fails to initiate along the anterior midline at E8.0, and Fgf8 is delocalized from the anterior neural ridge at E8.5, revealing a crucial role for atrophin 2 in the formation and function of these two signaling centers. Atrophin 2 is also required for normal organization of the apical ectodermal ridge, a signaling center that directs limb pattern. Elevated expression of atrophin 2 in neurons suggests it may interact with atrophin 1 in neuronal development or function. We further show that atrophin 2 associates with histone deacetylase 1 in mouse embryos, providing a biochemical link between Atr2 and a chromatin-modifying enzyme. Based on our results, and on those of others, we propose that atrophin proteins act as transcriptional co-repressors during embryonic development.
The 3rd Workshop on Heritable Disorders of Connective Tissue was held at the National Institutes of Health from 16th to 18th November, 2000. The Workshop was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH Office of Rare Diseases, March of Dimes, Coalition for Heritable Disorders of Connective Tissue, and the Foundation for Basic Cutaneous Research. It was supported by specific grants R13 AR46912 (US Public Health Service) and 4-FY00-4511 (March of Dimes Birth Defects Foundation). The Workshop was divided into six sessions, featuring 29 invited presentations. In addition to the invited participants, more than eighty guests (scientists, NIH staff, and members of the Coalition for Heritable Disorders of Connective Tissue) attended.
From its origin as a single ectodermal patch, the inner ear becomes a labyrinth of chambers housing six to eight sensory organs. Along the way, specific cell fates are realized. The secrets underlying these cell fate specifications are beginning to be revealed through the application of several molecular-genetic approaches. Recent papers describing such approaches have included gene expression studies in the early otic epithelium and inner ear sensory epithelia. large-scale screens of zebrafish mutants to identify ear defects, and targeted gene perturbations of neurotrophins. of their receptors or of the Brn-3.1 transcription factor in mice.
BACKGROUND: von Recklinghausen's neurofibromatosis is a hereditary disease that may affect any organ or system of the body primarily or secondarily, including the vascular system. Among the rare cerebrovascular abnormalities, the most common is stenosis or occlusion of the cerebral artery. Intracranial aneurysms are uncommon. CASE DESCRIPTION: A case of an intracranial cerebral aneurysm associated with von Recklinghausen's neurofibromatosis is reported. A 55-year-old woman presented with a history of intermittent headache for 2 months and right oculomotor nerve palsy for 1 month. Widespread cutaneous neurofibromas and angiomas were found over her trunk and limbs with prominent cafe-au-lait spots. X-ray showed that her left lung was compressed by a large mass in the left chest with rib defects and lateral spinal curvature. Right internal carotid angiography revealed a saccular aneurysm between C1 and C2. Craniotomy to clip the aneurysm could not be performed because the mass in her chest made intubation for general anaesthesia almost impossible. CONCLUSION: The clinical features of this case are discussed together with a review of 15 similar cases in the literature. There are different theories about this disorder. We agree that the malformations are derived not only from ectodermal, but also from mesodermal pathology. In terms of our case, we consider the progression of this disease to be slow.
Previously, we showed that Xenopus nodal-related factors (Xnrs) can act as mesoderm inducers, and that activin induces Xnr transcription, suggesting that Xnrs relay or maintain induction processes initiated by activin-like molecules. We used a dominant negative cleavage mutant Xnr2 (cmXnr2) to carry out loss-of-function experiments to explore the requirement for Xnr signaling in early amphibian embryogenesis, and the relationship between activin and Xnrs. cmXnr2 blocked mesoderm induction caused by Xnr, but not activin, RNA. In contrast, cmXnr2 did suppress mesoderm and endoderm induction by activin protein, while Xnr transcript induction was unaffected by cmXnr2, consistent with an interference with the function of Xnr peptides that were induced by activin protein treatment. The severe hyperdorsalization and gastrulation defects caused by Xnr2 in whole embryos were rescued by cmXnr2, establishing a specific antagonistic relationship between the normal and cleavage mutant proteins. Expression of cmXnr2 resulted in delayed dorsal lip formation and a range of anterior truncations that were associated with delayed and suppressed expression of markers for dorsoanterior endoderm, in which the recently recognized head organizer activity resides. Reciprocally, Xnr2 induced dorsoanterior endodermal markers, such as cerberus, Xhex-1 and Frzb, in animal cap ectoderm. The migratory behavior of head mesendoderm explanted from cmXnr2 RNA-injected embryos was drastically reduced. These results indicate that Xnrs play crucial roles in initiating gastrulation, probably by acting downstream of an activin-like signaling pathway that leads to dorsal mesendodermal specification, including setting up the head organizer.
A child born without scalp, or dura to cover the brain (aplasia cutis congenita) was successfully treated by a multidiscipline team. A coexisting rupture omphalocele forced a change in treatment from the currently recommended regimen of mandatory early scalp closure. Homograft skin was used to protect the brain during the time the omphalocele was treated and skin flaps were delayed. Fluoroscein dye was utilized to determine flap viability and predicted ischemia until after a third delaying procedure was performed. The successful outcome suggests that the present philosophy of early surgical closure being essential for survival in infants with large cranial defects can be altered and, in fact, permanent full-thickness flaps may be designed, tested for viability, and delayed while homograft skin protects the infant's brain from infection and thrombosis.
BMP7 is expressed at diverse sites in the developing mouse embryo, including visceral endoderm, notochord, heart, eye, kidney, and bone. A null mutation in BMP7 results in defects largely confined to the developing kidney and eye. To examine whether other bone morphogenetic protein (BMP) family members potentially substitute for BMP7 in mutant embryos, thereby restricting the observed defects, we analyzed the expression patterns of BMP2 through BMP7 in wild-type and mutant tissues. In the central nervous system and heart, which develop normally in the absence of BMP7 signaling, expression domains of other BMP family members completely overlap with that of BMP7. The variable expressivity of the eye defect correlates with partially overlapping BMP4 and BMP7 expression domains during early eye induction. The loss of BMP7 signaling in the kidney results in apoptosis in the metanephric mesenchyme, a cell population that exclusively expresses BMP7. Thus, tissue defects observed in BMP7 deficient embryos are restricted to cell populations exclusively expressing BMP7. These data suggest that BMP family members can functionally substitute for BMP7 at sites where they colocalize in vivo.
Although gap junctions are not known to be important in mediating cell-cell interactions amongst migratory cells, our studies showed that the connexin 43 (Cx43) gap junction gene is widely expressed in mouse neural crest cell lineages. Using in situ hybridization analysis, Cx43 expression was detected in presumptive neural crest cells emerging from the neural folds of the early postimplantation embryo. Neural crest expression of the Cx43 gap junction gene was also indicated by the analysis of transgenic mice containing a lacZ reporter construct driven by the Cx43 promoter. In neural tube explant cultures of these transgenic mice, lacZ expression was observed in the emerging neural crest outgrowths. Whole mount X-gal staining of these transgenic embryos at various stages of development showed lacZ expression in neural crest cells distributed along the entire craniocaudal axis, with expression found in both cranial and trunk neural crest cells contributing to a wide range of embryonic tissues. This included presumptive cardiac neural crest cells localized in the heart. In light of the widespread expression of Cx43 in neural crest cell lineages, dye injection studies, were carried out to determine if neural crest cells are functionally coupled via gap junctions. Such studies revealed extensive dye coupling among presumptive neural crest cells, thus demonstrating that these migratory cells are indeed gap junctional communication competent. In total, these observations suggest that gap junctions may play a role in mouse neural crest development. This possibility is particularly intriguing given the recent finding that the Cx43 knockout mice die of defects associated with the outflow tract [Reaume et al., 1995], a region of the heart in which neural crest cells are required for normal development.
Aplasia cutis congenita is a congenital condition in which skin, bone, and dura can be absent. The condition can present in isolation or with associated conditions such as limb anomalies or embryologic malformations. The majority of cases affect the scalp and are limited to the dermis and epidermis. Vertex aplasia cutis typically range in size from 0.5 to 3 cm. The rare larger scalp defects are prone to complications of hemorrhage and infection, and subsequently patients are at risk for death. For these reasons, surgical intervention for large defects may be required. We report the case of a 12-month-old Haitian boy who presented with aplasia cutis congenita of the scalp involving 10 cm of skin and 9 cm of underlying bone. There were no other associated anomalies.
OBJECTIVE: Severe cutis aplasia congenita has traditionally been treated with initial soft tissue coverage and delayed cranioplasty. We advocate the technique of early composite reconstruction of both bone and soft tissues. METHODS: Two cases of cutis aplasia congenita with large skull defects (6 x 10 cm, 8 x 8 cm) of superficial layers, skull, and dura are presented. In each case, composite reconstruction was undertaken before 2 weeks of age with restoration of bony and soft tissue coverage through autologous, full-thickness cranial bone grafts and scalp flaps. Both children have been followed up over 2 years with clinical examination and computed tomography (CT) scans. RESULTS: In both cases, defects were completely repaired postoperatively and remained closed 2 years later. Complete regeneration of calvarial bone graft donor sites were documented by CT scan. Head shape and circumference were normal at 2-year follow up.
BACKGROUND: CHARGE syndrome represents a constellation of malformations: C, coloboma of the iris or retina; H, heart defects; A, atresia of the choanae; R, retardation of growth and/or development; G, genital anomalies; and E, ear abnormalities. Recently, the Chromodomain helicase DNA-binding protein-7 (CHD7) at chromosome 8q12.1 was identified as a causative gene for CHARGE syndrome. Because CHD7 was identified as a causative gene using a positional cloning approach, the role of CHD7 in early embryogenesis needs to be further investigated. METHODS: Fertilized chick eggs were incubated to Hamburger and Hamilton stages 4-20 and were studied using whole mount in situ hybridization. Chicken EST clones corresponding to the chicken CHD7 (cChd7) sequence were identified using the chicken EST sequence database. From the EST clones, a digoxigenin-labeled RNA probe was synthesized and hybridized in situ to the embryonic specimens. RESULTS: The expression of cChd7 was pan-neuronal at stages 8-20. It was expressed throughout the rostral neural ectoderm and along the rostrocaudal axis but was absent from the more lateral, non-neuronal ectoderm. Adjacent to the neural tube, cChd7 transcripts were detected at the optic and otic placodes. At stage 20, cChd7 expression was observed in the branchial arches and olfactory placodes in addition to brain and optic and otic placodes. CONCLUSIONS: cChd7 was expressed in the neural epithelium, the otic placodes, the optic placodes, the branchial arches, and the olfactory placodes, which are the primordial tissues that give rise to organs affected in human CHARGE syndrome patients.
Vertebrate gastrulation involves the specification and coordinated movement of large populations of cells that give rise to the ectodermal, mesodermal and endodermal germ layers. Although many of the genes involved in the specification of cell identity during this process have been identified, little is known of the genes that coordinate cell movement. Here we show that the zebrafish silberblick (slb) locus encodes Wnt11 and that Slb/Wnt11 activity is required for cells to undergo correct convergent extension movements during gastrulation. In the absence of Slb/Wnt11 function, abnormal extension of axial tissue results in cyclopia and other midline defects in the head. The requirement for Slb/Wnt11 is cell non-autonomous, and our results indicate that the correct extension of axial tissue is at least partly dependent on medio-lateral cell intercalation in paraxial tissue. We also show that the slb phenotype is rescued by a truncated form of Dishevelled that does not signal through the canonical Wnt pathway, suggesting that, as in flies, Wnt signalling might mediate morphogenetic events through a divergent signal transduction cascade. Our results provide genetic and experimental evidence that Wnt activity in lateral tissues has a crucial role in driving the convergent extension movements underlying vertebrate gastrulation.