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PubMed2006

X-chromosome inactivation: role in skin disease expression.

UNLABELLED: The occurrence of X inactivation in mammals has the consequence that all women are functional mosaics. In X-linked skin disorders, Lyonization usually gives rise to a mosaic pattern, as manifest by the appearance of the lines of Blaschko. This arrangement of lesions is observed in male-lethal X-linked traits, such as incontinentia pigmenti, focal dermal hypoplasia, Conradi-Hünermann-Happle syndrome, oral-facial-digital syndrome type 1 and MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, as well as in various X-linked non-lethal phenotypes, such as hypohidrotic ectodermal dysplasia of Christ-Siemens-Touraine, IFAP (ichthyosis follicularis-alopecia-photophobia) syndrome and X-linked dyskeratosis congenita. Analogous X-inactivation patterns have been documented in human bones, teeth, eyes and, possibly, the brain. Patterns that are distinct from the lines of Blaschko are also seen, such as the lateralization observed in CHILD (congenital hemidysplasia with ichthyosiform nevus and limb defects) syndrome, and the chequerboard pattern seen in women heterozygous for X-linked congenital hypertrichosis. Exceptional cases of either severe or absent involvement in a woman heterozygous for an X-linked trait can be explained by skewing of X inactivation. Some X-linked skin disorders are caused by genes that escape inactivation, which is why heterozygous female 'carriers' of these disorders do not show mosaicism. A well-known example is X-linked recessive ichthyosis due to steroid sulphatase deficiency, the locus for which is situated at the tip of the short arm of the X chromosome and does not undergo Lyonization. On the other hand, in the case of Fabry disease, the gene encoding alpha-galactosidase A is subject to inactivation. Remarkably, however, the skin lesions of women do not show a mosaic pattern. CONCLUSION: In the various X-linked skin disorders, affected women show quite dissimilar degrees of involvement and forms of manifestation because X inactivation may give rise to different patterns of functional mosaicism. Paradoxically, no such pattern is observed in women with Fabry disease. Like many X-linked diseases, Fabry disease should neither be called recessive nor dominant, because these dichotomous terms are obscured by the mechanism of X inactivation.

Fabry Disease↗
PubMed2001

Embryonic hydromyelia: cystic dilatation of the lumbosacral neural tube in human embryos.

In a large collection of human embryos (the Kyoto Collection of Human Embryos, Kyoto University), we encountered five cases with abnormal dilatation of the neural tube at the lumbosacral level. In these examples, the central canal was enlarged, and the roof plate of the neural tube was extremely thin and expanded. The mesenchymal tissue was scarce or lacking between the roof plate and the surface ectoderm. This type of anomaly was assumed to be formed after neural tube closure and may be an early form of spina bifida. In two of the cases, some abnormal cells were found ectopically between the thin roof plate and the surface ectoderm. Morphologically, these cells resembled those forming spinal ganglia and could be of the neural crest origin. Since neural crest cells are pluripotent and can differentiate into a variety of tissues, such ectopic cells might undergo abnormal differentiation into teratomatous tumors and/or lipomas, which are frequently associated with spina bifida. We also discuss the definition of spina bifida and the classification of neural tube defects from the embryological and pathogenic viewpoints and propose a new classification of neural tube defects.

Dilatation, Pathologic↗
PubMed2003

Anaesthetic implications of Costello syndrome.

Costello syndrome is a disorder that primarily involves ectodermal tissues and is characterized by mental and growth retardation, distinctive coarse facies, redundant skin (neck, palms and soles), and papillomata (perioral, nasal and anal). Of primary concern to anaesthesiologists are potential airway difficulties related a short neck, macroglossia, hypertrophied tonsillar and supraglottic tissues, laryngeal papillomata and choanal atresia. A significant percentage of patients also have cardiac involvement which may manifest as congenital heart defects, arrhythmias, valvular dysfunction, or hypertrophic cardiomyopathy. Central nervous system involvement includes developmental delay and seizure disorders while endocrine abnormalities have been reported including hypothalamic-pituitary dysfunction resulting in hypopituitarism, hypothyroidism, and hypoadrenalism. The authors present a 2-year old child with Costello syndrome who required anaesthesia for direct laryngoscopy, rigid bronchoscopy, bilateral pressure equalization tubes and tonsillectomy. The perioperative implications of the syndrome are discussed.

Abnormalities, Multiple↗
PubMed2001

A subtractive gene expression screen suggests a role of transcription factor AP-2 alpha in control of proliferation and differentiation.

The transcription factor AP-2 alpha has been implicated as 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. AP-2 alpha is prominently expressed in cranial neural crest cells, a population of cells that migrate from the lateral margins of the brain plate during closure of the neural tube at day 8-9 of embryonic development. Homozygous AP-2 alpha mutant mice die perinatally with cranio-abdominoschisis, full facial clefting, and defects in cranial ganglia and sensory organs, indicating the importance of this gene for proper development. By using a subtractive cloning approach, we identified a set of genes repressed by AP-2 alpha that are described to retard cellular proliferation and induce differentiation and apoptosis. We show that these target genes are prematurely expressed in AP-2 alpha mutant mice. One of the genes isolated, the Krüppel-box transcription factor KLF-4 implicated in induction of terminal differentiation and growth regulation, is found expressed in mutant embryonic fibroblasts. We show that fibroblasts lacking AP-2 alpha display retarded growth but no enhanced apoptosis. Based on these data we suggest that AP-2 alpha might be required for cell proliferation by suppression of genes inducing terminal differentiation, apoptosis, and growth retardation.

Animals↗
PubMed2003

Msx2 and Twist cooperatively control the development of the neural crest-derived skeletogenic mesenchyme of the murine skull vault.

The flat bones of the vertebrate skull vault develop from two migratory mesenchymal cell populations, the cranial neural crest and paraxial mesoderm. At the onset of skull vault development, these mesenchymal cells emigrate from their sites of origin to positions between the ectoderm and the developing cerebral hemispheres. There they combine, proliferate and differentiate along an osteogenic pathway. Anomalies in skull vault development are relatively common in humans. One such anomaly is familial calvarial foramina, persistent unossified areas within the skull vault. Mutations in MSX2 and TWIST are known to cause calvarial foramina in humans. Little is known of the cellular and developmental processes underlying this defect. Neither is it known whether MSX2 and TWIST function in the same or distinct pathways. We trace the origin of the calvarial foramen defect in Msx2 mutant mice to a group of skeletogenic mesenchyme cells that compose the frontal bone rudiment. We show that this cell population is reduced not because of apoptosis or deficient migration of neural crest-derived precursor cells, but because of defects in its differentiation and proliferation. We demonstrate, in addition, that heterozygous loss of Twist function causes a foramen in the skull vault similar to that caused by loss of Msx2 function. Both the quantity and proliferation of the frontal bone skeletogenic mesenchyme are reduced in Msx2-Twist double mutants compared with individual mutants. Thus Msx2 and Twist cooperate in the control of the differentiation and proliferation of skeletogenic mesenchyme. Molecular epistasis analysis suggests that Msx2 and Twist do not act in tandem to control osteoblast differentiation, but function at the same epistatic level.

Animals↗
PubMed1997

Missense mutations in keratin 17 cause either pachyonychia congenita type 2 or a phenotype resembling steatocystoma multiplex.

Pachyonychia congenita (PC) is a group of autosomal dominant ectodermal dysplasias in which the main phenotypic characteristic is hypertrophic nail dystrophy. In the Jackson-Lawler form (PC-2), pachyonychia is accompanied by multiple pilosebaceous cysts, natal teeth, and hair abnormalities. By direct sequencing of genomic PCR products, we report heterozygous K17 missense mutations in the same conserved protein motif in a further five PC-2 families (K17 N92S in one familial and three sporadic cases; K17 Y98D in one familial case) confirming that mutations in this gene are a common cause of PC-2. We also show heterozygous missense mutations in K17 (N92H and R94H) in two families diagnosed as steatocystoma multiplex. Mild nail defects were observed in some but not all of these patients on clinical re-evaluation of these families. All the K17 mutations reported here were shown to co-segregate with the disease in the pedigrees analyzed and were excluded from 100 unaffected, unrelated chromosomes by restriction enzyme analysis of K17 genomic PCR products. We conclude that phenotypic variation is observed with K17 mutations, as is the case with other keratin disorders.

Cysts↗
PubMed2006

Improvement of peripheral nerve regeneration by a tissue-engineered nerve filled with ectomesenchymal stem cells.

Ectomesenchymal stem cells (EMSCs) originate from the cranial neural crest. They are a potential source of neuronal and Schwann cells (SCs) of the peripheral nervous system (PNS) during embryonic development. The third passage of EMSCs enzymatically isolated from the mandibular processes of Sprague-Dawley rats were cultured in forskolin and bovine pituitary extract for 6 days to generate functional Schwann cell phenotypes. Next, 10-mm defects in the sciatic nerves were bridged with an autograft, tissue-engineered nerve filled with differentiated cells in collagen, or a PLGA conduit alone in 18 rats, and the nerve defects of another four rats were left untreated. The regenerated nerves were evaluated by the sciatic functional index (SFI) monthly and by histological analysis 4 months after grafting. The recovery index of the sciatic nerve improved significantly in the autograft and tissue-engineered nerve groups, both of which were superior to the PLGA group. In animals transplanted with the EMSCs, there was greater regeneration than with conduit alone during the same period of implantation. These results show that when EMSCs are transplanted to a peripheral nerve defect they differentiate into supportive cells that contribute to the promotion of axonal regeneration.

Absorbable Implants↗
PubMed1989

Expression and embryonic function of empty spiracles: a Drosophila homeo box gene with two patterning functions on the anterior-posterior axis of the embryo.

Using the even-skipped homeo box as a probe to identify diverged homeo box genes in the Drosophila genome, we isolated the empty spiracles (ems) gene. Structural and functional comparisons between ems and other embryonic patterning genes of Drosophila suggest that ems acts, in part, as a homeotic selector gene, specifying the identity of some of the most anterior head segments. Mutant embryos lacking ems protein have severe patterning defects in the anterior head and are missing tracheal structures, including the filzkörper, which are normally developed by the eighth abdominal segment. ems has two different spatial patterns of expression during embryogenesis. The early, head-specific pattern consists of a single anterior stripe at the syncytial and cellular blastoderm stages. The later, metameric pattern consists of bilateral patches of ems expression in neural and ectodermal cells of every head and body segment. Variations of the ems expression pattern in bicoid mutants suggests that the morphogen protein produced by bicoid has a concentration-dependent regulatory role in the establishment of head-specific ems expression. In contrast, the metameric ems pattern is initiated independently of bicoid protein, and ems becomes expressed at high levels in the primordia of the duplicated fïlzkörper that develop in the anterior half of bicoid mutant embryos.

Amino Acid Sequence↗
PubMed1989

Ultrastructural defects in the apical neural folds in mutant embryos with spina bifida.

Ultrastructural pathology in the apical neural folds was analyzed by means of tannic acid (TA) and ruthenium red (RR) cytochemistry in abnormal (vl/vl) mutant mouse embryos ranging in age from 17-35 somites. At lumbosacral levels of the spinal cord where closure fails to occur, as well as at more cranial levels where closure occurs but results in dorsal midline abnormalities, normal deposition of TA-positive and RR-positive material occurred in the space that develops between the overlying surface ectoderm (SE) and neuroepithelium (NE). However, in lumbosacral regions, pleomorphic excrescences projected abnormally from the apices of the transitional zone cells between SE and NE cells of the open neural folds. These abnormal projections consisted of enlarged cytoplasmic blebs, as well as entire cells. The cells were not necrotic nor did they show evidence of incipient degeneration. However, it is possible that they represent aberrant putative neural crest cells, as indicated by their location in the transitional zone and by the filopodia and lamellipodia projecting from their luminal surfaces.

Abnormalities, Multiple↗
PubMed2006

Retinoic acid is required for endodermal pouch morphogenesis and not for pharyngeal endoderm specification.

Because tissues from all three germ layers contribute to the pharyngeal arches, it is not surprising that all major signaling pathways are involved in their development. We focus on the role of retinoic acid (RA) signaling because it has been recognized for quite some time that alterations in this pathway lead to craniofacial malformations. Several studies exist that describe phenotypes observed upon RA perturbations in pharyngeal arch development; however, these studies did not address whether RA plays multiple roles at distinct time points during development. Here, we report the resulting phenotypes in the hindbrain, the neural crest-derived tissues, and the pharyngeal endoderm when RA synthesis is disrupted during zebrafish gastrulation and pharyngeal arch morphogenesis. Our results demonstrate that RA is required for the post-gastrulation morphogenesis and segmentation of endodermal pouches, and that loss of RA does not affect the length of the pharyngeal ectoderm or medial endoderm along the anterior-posterior axis. We also provide evidence that RA is not required for the specification of pharyngeal pouch endoderm and that the pharyngeal endoderm consists of at least two different cell populations, of which the pouch endoderm is sensitive to RA and the more medial pharyngeal endoderm is not. These results demonstrate that the developmental processes underlying pharyngeal arch defects differ depending on when RA signaling is disturbed during development.

Animals↗
PubMed1997

Differential regulation of chordin expression domains in mutant zebrafish.

Patterning along the dorsal-ventral (D-V) axis of Xenopus and Drosophila embryos is believed to occur through a conserved molecular mechanism, with homologous proteins Chordin and Short gastrulation (Sog) antagonizing signaling by bone morphogenetic protein 4 (BMP-4) and Decapentaplegic (Dpp), respectively. We have isolated a zebrafish gene that is highly homologous to chordin and sog within cysteine-rich domains and exhibits conserved aspects of expression and function. As in Xenopus embryos, zebrafish chordin is expressed in the organizer region and transiently in axial mesoderm. Injection of zebrafish chordin mRNA to the ventral side of Xenopus embryos induced secondary axes. Ectopic overexpression in zebrafish resulted in an expansion of paraxial mesoderm and neurectoderm at the expense of more lateral and ventral derivatives, producing a range of defects similar to those of dorsalized zebrafish mutants (Mullins et al., 1996). In accordance with the proposed function of chordin in D-V patterning, dorsalized zebrafish mutants showed expanded domains of chordin expression by midgastrulation, while some ventralized mutants had reduced expression; however, in all mutants examined, early organizer expression was unaltered. In contrast to Xenopus, zebrafish chordin is also expressed in paraxial mesoderm and ectoderm and in localized regions of the developing brain, suggesting that there are additional roles for chordin in zebrafish embryonic development. Surprisingly, paraxial mesodermal expression of chordin appeared unaltered in spadetail mutants that later lack trunk muscle (Kimmel et al., 1989), while axial mesodermal expression was affected. This finding reveals an unexpected function for spadetail in midline mesoderm and in differential regulation of chordin expression during gastrulation.

Amino Acid Sequence↗
PubMed1998

Involvement of thyroid hormone and its alpha receptor in avian neurulation.

We have analyzed the expression pattern of c-erb A alpha and c-erb A beta which encode the thyroid hormone receptors (T3R alpha and T3R beta) during early chicken embryogenesis. Only c-erb A alpha expression was detected by RT-PCR and whole-mount in situ hybridization. c-erb A alpha transcripts were found to be already present at low level in embryos before egg incubation. During neurulation a marked increase was observed in neurectoderm. A reporter cell line was then constructed and used to demonstrate the release of significant amount of thyroid hormone (T3) from egg yolk by area opaca cells before gastrulation. During gastrulation T3 was found to be enriched in the primitive streak and Hensen's node. Introduction of excess T3 frequently resulted in abnormal development of anterior structures, mainly neural tube defects and anencephalia. These observations suggest that T3R alpha, like the closely related retinoic acid receptors, fulfills functions which are important for embryonic development well before the onset of thyroid gland function.

Animals↗
PubMed1992

[DNA repair and related diseases].

DNA-repair is a complex enzymatic process which enables all living cells to withstand the deleterious and mutagenic effects of most genotoxic agents. Defective DNA-repair is caused by mutations involving genes which encode the enzymes responsible for recognition and excision of DNA lesions. Some of these genes have been identified in humans. Several severe human diseases are caused by defective DNA repair affecting the entire genome (e.g. xeroderma pigmentosum and trichotiodystrophy) or only actively transcribed genes (Cockayne's syndrome). Some of these conditions are associated with extremely high rate of cancer.

Cockayne Syndrome↗
PubMed2003

Dlx5/6-enhancer directed expression of Cre recombinase in the pharyngeal arches and brain.

Dlx5 and Dlx6, two members of the Distalless gene family, are required for development of numerous tissues during embryogenesis, including facial and limb development. This gene pair is expressed in tandem, transcribed toward each other and separated by a short intergenic region containing multiple putative enhancers. Targeted inactivation of Dlx5 and Dlx6 in mice results in multiple developmental defects in craniofacial and limb structures, suggesting that these genes are crucial for aspects of both neural crest and nonneural crest development. To further investigate potential developmental roles of Dlx5 and Dlx6, we used one of the Dlx5/6 intergenic enhancers to drive Cre recombinase expression in transgenic mice. Crossing Dlx5/6-Cre transgenic mice with mice from the R26R strain results in beta-galactosidase staining in the apical ectodermal ridge, brain, and neural crest-derived mesenchyme of the pharyngeal arches, with staining in term embryos observed in the facial skeleton and specific brain structures. However, in contrast to endogenous expression patterns of Dlx5 and Dlx6, Cre expression within the pharyngeal arches occurs during a very narrow window in early development. Our studies suggest that Dlx5/6-Cre mice may prove useful both in further understanding the function and regulation of Distalless genes during development and in studies of gene function in conditional knockout mice.

Animals↗
PubMed2002

Exencephaly in a subset of animals heterozygous for AP-2alpha mutation.

BACKGROUND: Transcription factor AP-2alpha has been implicated as 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, chick, and frog embryos. AP-2alpha is prominently expressed in cranial neural crest cells, a population of cells migrating from the lateral margins of the neural folds during closure of the neural tube in E (embryonic day of development) 8-9 mouse embryos. Homozygous AP-2alpha mutant mice die perinatally with cranio-abdominoschisis, full facial clefting, and defects in cranial ganglia and sensory organs. METHODS: Mice heterozygous for the AP-2alpha mutation on a 129/Sv strain were crossed with wildtype mice from the strain 129/Ola. The resulting embryos were genotyped, examined and used for histological analysis. RESULTS: A subset of animals heterozygous for the AP-2alpha mutation develop a midbrain exencephaly after the mutation was crossed for one generation in the 129/Ola mouse strain. Up to 14% of the animals show a failure of the cranial neural folds to close resulting in a partial exencephaly, all of them being heterozygous for the mutation. The affected animals show reduced rostrocaudal dimensions of the skull and malformations of the bones of the cranial vault. The neural tube defects vary from pure midbrain exencephaly to a forebrain/midbrain exencephaly where the proliferating neural tissue covers the eyes completely. CONCLUSIONS: The results support a role of AP-2alpha in the etiology of exencephalic disorders. The phenotype observed might be due to a downregulation of the remaining allele suggesting the presence of an upstream modifier gene.

Animals↗
PubMed1998

Dynamic developmental expression of smallminded, a Drosophila gene required for cell division.

Here we describe the expression pattern of the smallminded (smid) gene during Drosophila development and investigate the phenotype of a null mutant. In situ hybridisation reveals the ubiquitous expression of smid transcript throughout early embryonic stages until the extended germ band stage, after which expression becomes localised to the neurogenic ectoderm and gonad. Post-embryonic expression is restricted to tissues engaged in the developmental programme of the adult fly: the re-enlarged neuroblasts; imaginal disks; histoblast nests; and precursors of adult muscles. The correlation of smid expression with mitotic activity suggests a cell cycle function which is confirmed by the observed phenotype of a smid null mutant characterised by an abnormally small CNS, due to defective mitosis of post-embryonic neuroblasts and their subsequent death by apoptosis.

Animals↗
PubMed1999

Expression of chicken fibroblast growth factor homologous factor (FHF)-1 and of differentially spliced isoforms of FHF-2 during development and involvement of FHF-2 in chicken limb development.

Members of the fibroblast growth factor (FGF) family have been identified as signaling molecules in a variety of developmental processes, including important roles in limb bud initiation, growth and patterning. This paper reports the cloning and characterization of the chicken orthologues of fibroblast growth factor homologous factors-1 and -2 (cFHF-1/cFGF-12 and cFHF-2/cFGF-13, respectively). We also describe the identification of a novel, conserved isoform of FHF-2 in chickens and mammals. This isoform arises by alternative splicing of the first exon of the FHF-2 gene and is predicted to encode a polypeptide with a distinct amino-terminus. Whole-mount in situ hybridization reveals restricted domains of expression of cFHF-1 and cFHF-2 in the developing neural tube, peripheral sensory ganglia and limb buds, and shows that the two cFHF-2 transcript isoforms are present in non-overlapping spatial distributions in the neural tube and adjacent structures. In the developing limbs, cFHF-1 is confined to the posterior mesoderm in an area that encompasses the zone of polarizing activity and cFHF-2 is confined to the distal anterior mesoderm in a region that largely overlaps the progress zone. Ectopic cFHF-2 expression is induced adjacent to grafts of cells expressing Sonic Hedgehog and the zone of cFHF-2 expression is expanded in talpid2 embryos. In the absence of the apical ectodermal ridge or in wingless or limbless mutant embryos, expression of cFHF-1 and cFHF-2 is lost from the limb bud. A role for cFHF-2 in the patterning and growth of skeletal elements is implied by the observation that engraftment of developing limb buds with QT6 cells expressing a cFHF-2 isoform that is normally expressed in the limb leads to a variety of morphological defects. Finally, we show that a secreted version of cFHF-2 activates the expression of HoxD13, HoxD11, Fgf-4 and BMP-2 ectopically, consistent with cFHF-2 playing a role in anterior-posterior patterning of the limb.

Alternative Splicing↗
PubMed2004

[Large scalp and skull defect in patient with aplasia cutis congenita].

Aplasia cutis congenita is a rare condition characterized by the absence of skin layers. It is most common on the scalp, middle line, and it can be seen as a congenital ulcer involving periosteum, skull and dura. We present the case of a female newborn infant with a dysmorphic facies, a large scalp and skull defect exposing the dura. There was no cerebrospinal fluid leakage. The rarity of cases with large defects and small series reported make difficult to determinate the ideal treatment for aplasia cutis congenita. More studies are necessary to define the etiology and best management of this patients.

Ectodermal Dysplasia↗