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PubMed2006

Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.

Noonan syndrome is a developmental disorder characterized by short stature, facial dysmorphia, congenital heart defects and skeletal anomalies. Increased RAS-mitogen-activated protein kinase (MAPK) signaling due to PTPN11 and KRAS mutations causes 50% of cases of Noonan syndrome. Here, we report that 22 of 129 individuals with Noonan syndrome without PTPN11 or KRAS mutation have missense mutations in SOS1, which encodes a RAS-specific guanine nucleotide exchange factor. SOS1 mutations cluster at codons encoding residues implicated in the maintenance of SOS1 in its autoinhibited form. In addition, ectopic expression of two Noonan syndrome-associated mutants induces enhanced RAS and ERK activation. The phenotype associated with SOS1 defects lies within the Noonan syndrome spectrum but is distinctive, with a high prevalence of ectodermal abnormalities but generally normal development and linear growth. Our findings implicate gain-of-function mutations in a RAS guanine nucleotide exchange factor in disease for the first time and define a new mechanism by which upregulation of the RAS pathway can profoundly change human development.

Animals↗
PubMed1992

A variant limb deformity transcript expressed in the embryonic mouse limb defines a novel formin.

The formins constitute a set of protein isoforms encoded by the alternatively spliced transcripts arising from the limb deformity (ld) locus of the mouse. Mutations in this locus disrupt formation of the anteroposterior axis of the embryonic limb. Although ld transcripts are widely expressed during embryogenesis, we have identified a novel transcript that is expressed in the mesenchyme and apical ectodermal ridge of the developing limb. This pattern of expression coincides with the earliest morphological defects observed in ld mutant limb buds. Moreover, the formin encoded by this transcript bears a highly acidic amino terminus, as distinguished from the basic amino terminus encoded by other ld transcripts suggesting that it may have a distinct biochemical function.

Amino Acid Sequence↗
PubMed2001

Foregut endoderm is required at head process stages for anteriormost neural patterning in chick.

Anterior definitive endoderm, the future pharynx and foregut lining, emerges from the anterior primitive streak and Hensen's node as a cell monolayer that replaces hypoblast during chick gastrulation. At early head process stages (4+ to 6; Hamburger and Hamilton) it lies beneath, lateral to and ahead of the ingressed axial mesoderm. Removal of the monolayer beneath and ahead of the node at stage 4 is followed by normal development, the removed cells being replaced by further ingressing cells from the node. However, similar removal during stages 4+ and 5 results in a permanent window denuded of definitive endoderm, beneath prechordal mesoderm and a variable sector of anterior notochord. The foregut tunnel then fails to form, heart development is confined to separated lateral regions, and the neural tube undergoes no ventral flexures at the normal positions in brain structure. Reduction in forebrain pattern is evident by the 12-somite stage, with most neuraxes lacking telencephalon and eyes, while forebrain expressions of the transcription factor genes GANF and BF1, and of FGF8, are absent or severely reduced. When the foregut endoderm removal is delayed until stage 6, later forebrain pattern appears once again complete, despite lack of foregut formation, of ventral flexure and of heart migration. Important gene expressions within axial mesoderm (chordin, Shh and BMP7) appear unaffected in all embryos, including those due to be pattern-deleted, during the hours following the operation when anterior brain pattern is believed to be determined. A specific system of neural anterior patterning signals, rather than an anterior sector of the initially neurally induced area, is lost following operation. Heterotopic lower layer replacement operations strongly suggest that these patterning signals are positionally specific to anteriormost presumptive foregut. The homeobox gene Hex and the chick Frizbee homologue Crescent are both expressed prominently within anterior definitive endoderm at the time when removal of this tissue results in forebrain defects, and the possible implications of this are discussed. The experiments also demonstrate how stomodeal ectoderm, the tissue that will, much later, form Rathke's pouch and the anterior pituitary, is independently specified by anteriormost lower layer signals at an early stage.

Animals↗
PubMed1999

Alterations in the incisor development in the Tabby mouse.

The X-linked tabby (Ta) syndrome in the mouse is homologous to the hypohidrotic ectodermal dysplasia (HED) in humans. As in humans with HED, Ta mice exhibit hypohidrosis, characteristic defects of hairs and tooth abnormalities. To analyze the effects of Ta mutation on lower incisor development, histology, morphometry and computer-aided 3D reconstructions were combined. We observed that Ta mutation had major consequences for incisor development leading to abnormal tooth size and shape, change in the balance between prospective crown- and root-analog tissues and retarded cytodifferentiations. The decrease in size of Ta incisor was observed at ED13.5 and mainly involved the width of the tooth bud. At ED14.5-15.5, the incisor appeared shorter and narrower in the Ta than in the wild type (WT). Growth alterations affected the diameter to a greater extent than the length of the Ta incisor. From ED14.5, changes in the shape interfered with the medio-lateral asymmetry and alterations in the posterior growth of the cervical loop led to a loss of the labio-lingual asymmetry until ED17.0. Although the enamel organ in Ta incisors was smaller than in the WT, a larger proportion of the dental papilla was covered by preameloblasts-ameloblasts. These changes apparently resulted from reduced development of the lingual part of the enamel organ and might be correlated with a possible heterogeneity in the development of the enamel organ, as demonstrated for upper incisors. Our observations suggest independent development of the labial and lingual parts of the cervical loop. Furthermore, it appeared that the consequences of Ta mutation could not be interpreted only as a delay in tooth development.

Animals↗
PubMed2006

Adams-Oliver syndrome and isolated aplasia cutis congenita in two siblings.

Adams-Oliver syndrome is a rare congenital anomaly complex characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects. We present a 9-year-old girl with a large, congenital scalp defect on her vertex, without underlying bone defect. Brachydactyly and syndactylia of her toes were also evident. Her 13-year-older brother had an 8 x 5 cm scalp defect without any limb defects (isolated ACC).

Adolescent↗
PubMed1999

Spatiotemporal expression pattern of keratins in skin of AP-2alpha-deficient mice.

Transcription factor AP-2alpha has been implicated as being a cell-type-specific regulator of gene expression during vertebrate embryogenesis based on its expression pattern in neural crest cells, ectoderm, and the nervous system in mouse and frog embryos. In mice, AP-2alpha is expressed in surface ectoderm beginning at the single cell layer state around E8.75. AP-2alpha-deficient mice, derived by targeted mutagenesis, display a severe ventral closure defect resulting in cranio-abdominoschisis and a hypoplasia of the cranial ganglia. This study analyzed the effect of a targeted disruption of the AP-2alpha gene on the architecture and the expression of intermediate filaments in skin. We analyzed skin samples from newborn mice and found no difference in either the morphology of the skin or the amount of intermediate filaments expressed. This suggests that despite the results from other analyses, loss of transcription factor AP-2alpha does not affect the expression of intermediate filaments in the skin of newborn animals. We found an altered spatial distribution of intermediate filament expression in the single layered cranial ectoderm during days 9-12 of gestation leading to an evenly distributed expression of keratin 5 and 15 in the mutants. Furthermore, the mutants lack a ring of ectodermal cells highly positive for keratin 15 in the area where lens induction occurs, indicating a defect in the inductive interactions underlying eye formation.

Animals↗
PubMed1998

Developmental study on reduction and kinks of the tail in a new mutant knotty-tail mouse.

The knotty-tail (knt/knt) mouse has a short and knotty tail. The tail deformity is caused by a decrease in the number of caudal vertebrae and a deformity of them in the distal part of the tail. The objective of the study was to determine how reduction and kinks of the tail region were formed during secondary body formation. By day 12.0 pc, the somitogenesis of knt/knt embryos was completed; the number of caudal somites more or less agreed with those of the caudal vertebrae in knt/knt mice and were similar to those of knt/+ embryos. On the other hand, the somitogenesis of knt/+ embryos continued up to day 12.5 pc. The somites below about the sixth caudal somite were wedge-shaped with a dorsal apex in knt/knt embryos. The location of abnormal somites also corresponded well to that of deformed caudal vertebrae. Abnormal somitogenesis was always preceded by abnormalities in the presomitic region. Under gross observation, this could be seen to become markedly thickened, and histologically its dorsoventral diameter increased in the transverse plane on days 10.5-12.0 pc. In the mesenchyme there was often obvious cell death at the boundary of the unsegmented area and the tail bud after day 10.5 pc. These results suggested that the shortness of tail was primarily caused by the agenesis of distal caudal vertebrae following the agenesis of distal caudal somites, and partly by the disappearance of the presomitic part due to cell death, while the tail kinks were caused by the deformation of each caudal vertebra following disturbances of the caudal somites. Also, it is highly probable that the prominent cell death at the boundary of the unsegmented area and the tail bud may involve a defect or deformity of somites in this mutant.

Animals↗
PubMed2005

Outcomes and DNA analysis of ex vivo expanded stem cell allograft for ocular surface reconstruction.

PURPOSE: To investigate the outcome of a new technique of ex vivo expanded stem cell allograft for limbal stem cell deficiency (LSCD), and to characterize the ocular surface genotype after surgery. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Ten eyes of 10 patients with profound LSCD arising from ectodermal dysplasia (3 eyes), Stevens-Johnson syndrome (3 eyes), chemical injury (2 eyes), thermal injury (1 eye), and rosacea blepharoconjunctivitis (1 eye). INTERVENTION: Allogeneic corneal limbal stem cells were cultured on plastic and transplanted to the recipient eye after removal of conjunctival pannus. Amniotic membrane was applied in a bandage capacity. The procedure was combined with other reconstructive surgery in 2 cases. Nine patients received systemic cyclosporin A immunosuppression, and the DNA genotype was investigated with surface impression cytology. MAIN OUTCOME MEASURES: Parameters of LSCD, including vascularization, conjunctivalization, inflammation, epithelial defect, photophobia, and pain. RESULTS: The mean follow-up period was 28 months (range, 12-50). Seven of 10 eyes (70%) had improved parameters of LSCD at final follow-up and were considered successes. Four (40%) had improved visual acuity, including 3 having had further procedures for visual rehabilitation. Three patients failed to improve-1 with a thermal burn and lid deformity, 1 with Stevens-Johnson syndrome and severe dry eye, and 1 with ectodermal dysplasia who developed an epithelial defect at 26 months. DNA analysis of the first 7 cases showed no ex vivo donor stem cell DNA present beyond 9 months. CONCLUSIONS: Ex vivo expanded stem cell allograft is a useful technique for restoring the ocular surface in profound LSCD. The absence of donor DNA beyond 9 months suggests that ongoing immunosuppression may be unnecessary and raises questions regarding the origin of the host corneal epithelium.

Adolescent↗
PubMed2004

Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity.

Clouston syndrome or hidrotic ectodermal dysplasia (HED) is a rare dominant genodermatosis characterized by palmoplantar hyperkeratosis, generalized alopecia and nail defects. The disease is caused by mutations in the human GJB6 gene which encodes the gap junction protein connexin30 (Cx30). To gain insight into the molecular mechanisms underlying HED, we have analyzed the consequences of two of these mutations (G11R Cx30 and A88V Cx30) on the functional properties of the connexons they form. Here, we show that the distribution of Cx30 is similar in affected palmoplantar skin and in normal epidermis. We further demonstrate that the presence of the wild-type protein (wt Cx30) improves the trafficking of mutated Cx30 to the plasma membrane where both G11R and A88V Cx30 co-localize with wt Cx30 and form functional intercellular channels. The electrophysiological properties of channels made of G11R and A88V Cx30 differ slightly from those of wt Cx30 but allow for dye transfer between transfected HeLa cells. Finally, we document a gain of function of G11R and A88V Cx30, which form functional hemichannels at the cell surface and, when expressed in HeLa cells, generate a leakage of ATP into the extracellular medium. Such increased ATP levels might act as a paracrine messenger that, by altering the epidermal factors which control the proliferation and differentiation of keratinocytes, may play an important role in the pathophysiological processes leading to the HED phenotype.

Adenosine Triphosphate↗
PubMed1996

Severe defects in the formation of epaxial musculature in open brain (opb) mutant mouse embryos.

The differentiation of somite derivatives is dependent on signals from neighboring axial structures. While ventral signals have been described extensively, little is known about dorsal influences, especially those from the dorsal half of the neural tube. Here, we describe severe phenotypic alterations in dorsal somite derivatives of homozygous open brain (opb) mutant mouse embryos which suggest crucial interactions between dorsal neural tube and dorsal somite regions. At Theiler stage 17 (day 10.5 post coitum) of development, strongly altered expression patterns of Pax3 and Myf5 were observed in dorsal somite regions indicating that the dorsal myotome and dermomyotome were not differentiating properly. These abnormalities were later followed by the absence of epaxial (dorsal) musculature; whereas, body wall and limb musculature formed normally. Analysis of Mox1 and Pax1 expression in opb embryos revealed additional defects in the differentiation of the dorsal sclerotome. The observed abnormalities coincided with defects in differentiation of dorsal neural tube regions. The implications of our findings for interactions between dorsal neural tube, surface ectoderm and dorsomedial somite regions in specifying epaxial musculature are discussed.

Animals↗
PubMed2005

Frequent respiratory tract infections in the canine model of X-linked ectodermal dysplasia are not caused by an immune deficiency.

As in many human patients with X-linked hypohidrotic ectodermal dysplasia (XHED), XHED dogs are at an increased risk for pulmonary disorders. Localized immune system defects had been suspected previously in affected dogs because of frequent infections and unexpected deaths due to opportunistic respiratory tract infections. Experiments were designed to examine systemic and localized humoral and cellular responses, development and function of T cells, and thymic morphology. All dogs used in these experiments were clinically healthy at the time of examination and their immune responses were compared to normal littermates. Serum immunoglobulin concentrations differed somewhat between normal dogs and dogs affected with XHED but they were all within normal ranges. The XHED dogs responded appropriately to vaccination with tetanus toxoid suggesting normal systemic B and plasma cell function. Thymic morphology was compared between normal and affected dogs and T cells were assessed for functionality. Numbers and phenotypes of T and B cells in blood and thymus of affected dogs were within normal limits suggesting normal development of T cells. Cytotoxic and phagocytic ability of macrophages and neutrophils was also normal in affected dogs. In contrast, the secretory IgA concentrations found in affected dogs were significantly higher than in normal dogs, while lacrimal secretions were significantly decreased. These results suggest a compensatory mechanism for secretory IgA, so that the total amount equals that in normal dogs. The results presented in this study indicate that the XHED dogs have a relatively intact immune system and suggest that the same is true for humans with the homologous form of XHED.

Animals↗
PubMed1990

The gene Serrate encodes a putative EGF-like transmembrane protein essential for proper ectodermal development in Drosophila melanogaster.

Mutations in the third chromosome gene Serrate are shown to display genetic interactions with specific alleles of the neurogenic locus Notch, which encodes a transmembrane protein with epidermal growth factor (EGF) homology. Embryonic lethal Serrate mutations exhibit epidermal and neuronal defects, which are reminiscent of those produced by mutations in the Drosophila EGF receptor homolog gene. We present the molecular cloning of Serrate and show that it encodes two coordinately expressed transcripts from a genomic interval greater than 30 kb in length. The deduced protein product of 1404 amino acids contains a single transmembrane domain and 14 EGF-like repeats. Thus, Serrate represents another member of the group of EGF-containing loci in Drosophila. Whole-mount in situ hybridization analysis reveals complex temporal and spatial patterns of RNA expression consistent with the epidermal and neuronal defects observed in mutant embryos. Finally, we discuss the implications of Serrate function within the context of other cell-surface molecules known to be involved in the differentiation of ectodermally derived tissues.

Alleles↗
PubMed2003

Fgfr1 regulates patterning of the pharyngeal region.

Development of the pharyngeal region depends on the interaction and integration of different cell populations, including surface ectoderm, foregut endoderm, paraxial mesoderm, and neural crest. Mice homozygous for a hypomorphic allele of Fgfr1 have craniofacial defects, some of which appeared to result from a failure in the early development of the second branchial arch. A stream of neural crest cells was found to originate from the rhombomere 4 region and migrate toward the second branchial arch in the mutants. Neural crest cells mostly failed to enter the second arch, however, but accumulated in a region proximal to it. Both rescue of the hypomorphic Fgfr1 allele and inactivation of a conditional Fgfr1 allele specifically in neural crest cells indicated that Fgfr1 regulates the entry of neural crest cells into the second branchial arch non-cell-autonomously. Gene expression in the pharyngeal ectoderm overlying the developing second branchial arch was affected in the hypomorphic Fgfr1 mutants at a stage prior to neural crest entry. Our results indicate that Fgfr1 patterns the pharyngeal region to create a permissive environment for neural crest cell migration.

Alleles↗
PubMed1998

A role for neural cell adhesion molecule in the formation of the avian inner ear.

The inner ear forms by a series of folds within an ectodermal placode. Previous work has shown that changes in surrounding tissues play a more prominent role in invagination than changes in the cytoskeleton of the primordium. Interference with the integrity of the extracellular matrix causes abnormalities in the folding process, primarily related to abnormalities in the paraxial mesoderm which lies ventral to the placode. In this study, the role of the neural cell adhesion molecule (N-CAM) was investigated, based on the expression of this component of the plasmalemma at the time the otic placode begins to fold. Microinjection of blocking antibodies to N-CAM into the paraxial mesoderm adjacent to the otic placode resulted in two major classes of defects, detachment of the primordium from the neural tube and interference with formation of the folds. Microinjection of saline, control immunoglobulin, or antibody against cytoplasmic domain had no effect. These defects correlate with the pattern of N-CAM expression at the time of injection, along the neural ectoderm and otic epithelium and the mesenchyme cells ventral to the primordium. It seems likely that N-CAM is playing a role in heterophilic associations rather than through the homophilic binding domain during formation of the otic vesicle.

Animals↗
PubMed1998

Disruption of primary mesenchyme cell patterning by misregulated ectodermal expression of SpMsx in sea urchin embryos.

The patterning of the mesoderm of the sea urchin embryo is a classical paradigm of epithelial mesenchymal interactions in organogenesis, yet little is known of its molecular basis. Here we address the role of the homeobox gene, SpMsx, a member of the highly conserved Msx gene family, in this process. Msx genes have been shown to function in the dorsoventral patterning of the central nervous system in Drosophila and in a variety epithelial-mesenchymal interactions in vertebrates. We showed previously that the SpMsx gene is expressed during embryogenesis in a complex and dynamic pattern consistent with roles in the development of subpopulations of endoderm, mesoderm, and oral ectoderm. To perturb this pattern of expression and thus probe the function of SpMsx, we injected SpMsx mRNA into single-cell zygotes and monitored development morphologically and with a series of territory-specific molecular markers. RT-PCR analysis revealed that injected SpMsx transcripts persisted at least until the gastrula stage in amounts comparable to endogenous levels. Injected embryos exhibited deficiencies in the organization of primary and secondary mesenchyme cells within the blastocoelic cavity, as well as abnormalities in spicule number and shape. Defects in the endoderm were also common, including reduced or absent archenterons. Micromere transplantation experiments revealed that the defects in skeletogenic mesenchyme patterning were non-cell autonomous, consistent with findings that cell-cell interactions between ectoderm and the progenitors of the skeletogenic mesenchyme, the primary mesenchyme cells (PMCs), are important both for PMC guidance and spicule morphogenesis. Our data, taken together with observations in other organisms on the role of Msx genes in embryonic signaling processes, particularly involving the BMP pathway, suggest that SpMsx may be a part of the mechanism by which the ectoderm influences both the arrangement of primary mesenchyme cells within the blastocoel and the shapes of the skeletal rods.

Animals↗
PubMed1989

Hypohidrotic ectodermal dysplasia: a review.

HED is an X-linked recessive disease involving abnormalities of tissues of ectodermal origin due to developmental disturbances in the embryonal state. These abnormalities include 1) trichodysplasia, 2) dental defects, 3) onychodysplasia, and 4) dyshidrosis. Also common are thin, dry skin, typical facial features such as saddle-nose deformity and periorbital wrinkling/pigmentation, otolaryngologic problems, eczema, and respiratory disease. Diagnosis of HED may be suspected in a child with recurrent fever of unknown etiology, thin blond hair, and anodontia. The diagnosis can be strengthened by low or absent sweat pore counts, and confirmed by palmar skin biopsy. Management is multidisciplinary and mainly involves avoidance of hyperpyrexia in the early years. At school age and beyond, the cosmetic features become more of a concern to the patient. As adults, these patients usually lead fairly normal lives both physically and socially, and have a life expectancy similar to that of the general population.

Ectodermal Dysplasia↗
PubMed1994

Ulerythema ophryogenes and keratosis pilaris in a child with monosomy 18p.

We report a 13-year-old boy with deletion of the short arm of chromosome 18 and follicular, partially inflammatory, keratotic papules of the eyebrows, foreskin, and cheeks (ulerythema ophryogenes) as well as the shoulders, upper back, upper arms, and thighs (keratosis pilaris), initially diagnosed as atopic dermatitis. Over 100 patients with this genetic defect have been reported, and the 18p- syndrome is considered one of the most frequently occurring deletion syndromes. However, ulerythema ophryogenes and keratosis pilaris have not been described in any of these patients, although the association of the latter with other genetic abnormalities is well known. Keratosis pilaris is a relatively common genodermatosis of ectodermal origin, frequently occurring with ichthyosis or atopy; concomitance with ulerythema ophryogenes has also been reported. The association of chromosome 18p deletion defect and ulerythema ophryogenes may be helpful in future attempts to localize the gene defect responsible for follicular genokeratoses.

Child↗