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PubMed1994

Embryonic neuroepithelial sodium transport, the resulting physiological potential, and cranial development.

We have shown that the amiloride/novobiocin-sensitive sodium transport system of adult animal integuments is first observed in embryonic surface ectoderm and show here that this physiology is retained in this ectoderm following the closure of the neural folds. Unidirectional transport of Na+ out of the neural tube lumen results in a potential difference on the order of 40-90 mV, negative with respect to the abluminal surface. This transneural tube potential can be collapsed by iontophoresis of Na+ channel blockers amiloride or benzamil into the lumen, leading to severe cranial defects and incomplete morphogenesis. Modestly increasing the transneural tube potential with injection of novobiocin into the lumen also produces a lesser degree of developmental abnormality. We discuss the ways in which this physiology may help control the organization of the early nervous system.

Ambystoma↗
PubMed2004

The role of Zic genes in neural development.

The Zic family of zinc-finger proteins plays a crucial role in neural development. Zic genes are vertebrate homologs of odd-paired, the Drosophila pair-rule gene. Their gene products have zinc-finger domains similar to those of Gli proteins, which act as transcriptional regulators in hedgehog signaling. Recent studies of human, mouse, frog, fish and ascidian Zic homologs have provided evidence that Zic genes are involved in a variety of developmental processes, including neurogenesis, myogenesis, skeletal patterning, and left-right axis establishment. Zic genes appear to have multiple roles in neural development. They control the initial phase during which ectoderm differentiates into neuroectoderm, and they may act as bridges between secreted neural tissue induction signals and the basic-helix-loop-helix class of neurogenesis-inducing transcriptional regulatory factors. Studies of loss-of-function mutations with differing Zic gene subtypes show that the Zic family of genes controls the process of neurulation. Mutations result in neural tube defects, which are seen at different rostrocaudal levels depending on which Zic gene subtype has been affected. Development of holoprosencephaly, forebrain anomalies, and cerebellar dysgenesis indicate that region-specific morphogenesis of the CNS is also controlled by Zic genes. The underlying molecular actions of Zic gene products, which allow them to control development, remain a mystery. Recent molecular characterization has shown that Zic proteins are able to bind Gli-binding DNA sequences in a sequence-specific manner, but with lower affinity than Gli proteins. Zic proteins also can activate transcription from several promoters. Furthermore, Zic and Gli proteins interact physically via their zinc-finger domains, raising the possibility that Zic proteins can act as transcriptional cofactors and modulate the hedgehog-signaling pathway. Clarification of the specific cooperating factors is therefore required in each case. Other evidence also suggests that Zic proteins can inhibit neuronal differentiation by activating Notch signals. This association might be is a clue toward understanding of the multifunctional property of Zic proteins because Notch signaling also is implicated in the control of several developmental processes.

Animals↗
PubMed2002

Functional studies of human skin disease- and deafness-associated connexin 30 mutations.

Connexin 30 (Cx30) is a component of the gap junction complex. Dominant and recessive mutations in the GJB6 gene encoding Cx30 are associated with a variety of human inherited diseases primarily affecting the epidermis, hair, nail, and/or the inner ear. The underlying mechanism of disease associated with different GJB6 mutations such as the disruption of gap junction mediated intercellular communication is unknown. Towards understanding these disease mechanisms, transfection studies were performed in a keratinocyte cell line and in HeLa cells using EGFP tagged wildtype Cx30 and mutant Cx30 constructs harbouring dominant disease-associated GJB6 mutations. For all three of the skin disease-associated Cx30 mutations investigated, impaired trafficking of the protein to the plasma membrane was observed thus preventing the formation of functional Cx30 gap junctions. In contrast, the deafness-associated mutation T5M-Cx30/EGFP trafficked to the membrane but defective channel activity was observed following dye transfer studies.

Base Sequence↗
PubMed2000

Large scalp and skull defect in aplasia cutis congenita.

Aplasia cutis congenita (ACC) is a rare disease, which may involve any site on the body but usually the vertex with scalp and even skull involvement. Superficial lesions may heal spontaneously and seldom result in morbidity or mortality. However, in patients with large scalp and skull defects, there are risks of infection and bleeding. Both surgical and conservative treatment have been proposed. We report a case of successful treatment of ACC by early debridement and wound closure with split-thickness skin graft (STSG) in the neonatal stage followed by replacement of the STSG with a hairy scalp flap by means of tissue expansion at the age of 3 years. The original skull defect, 7 x 10 cm in size, decreased to 1.2 x 1.2 cm after a 4.5-year follow-up. No complications, such as haemorrhage or meningitis, were encountered. The final result was satisfactory.

Ectodermal Dysplasia↗
PubMed2003

[Ventral prolapse of the embryo: case report].

OBJECTIVE: A pathologic human embryo 3 mm long affected by a "ventral prolaps" was present in a product of conception implanted within the Fallopian tube. The gestational age was 7 weeks. The malformation was characterized by a deep protrusion of the embryonal body (containing the medullary tube and the notochord adherent to the ceiling of the yolk sac) through the umbilical ring of the germ disc delineated by ectoderm covered mesenchymal streaks with primordia of the umbilical veins. Similar two affected embryos were depicted by Kollmann in his Handatlas in 1907, but were considered normal. DESIGN: Case report. SETTING: Institute for the Care of Mother and Child, Prague, Institute for Postgraduate Medical Education, Prague. RESULTS: Implanted product of conception found within the Fallopian tube exhibited a characteristic embryonic defect described as the "ventral prolaps". CONCLUSION: Ventral prolaps of the embryo represents a characteristic embryonal malformation of unknown developmental significance.

Embryo, Mammalian↗
PubMed2001

Mutations in the EDA gene in three unrelated families reveal no apparent correlation between phenotype and genotype in the patients with an X-linked anhidrotic ectodermal dysplasia.

Anhidrotic ectodermal dysplasia (EDA) is caused by mutations in the EDA gene encoding ectodysplasin A, a member of the TNF ligand superfamily involved in the communication between the cells. The structure of the EDA gene was investigated in three patients exhibiting clinical symptoms of EDA in an attempt to correlate the molecular findings with the phenotype of the patients. Genomic DNA was analyzed by single stranded conformation polymorphism (SSCP) followed by direct sequencing. In one of the patients, as well as in his heterozygous mother and sister, a single T insertion was evidenced in exon 3 between nucleotides 713 and 714 that changed Lys codon (AAA) into a termination codon TAA (Lys158Ter). In the other patient, A1321T transversion was demonstrated. The same mutation was found in his heterozygous mother and resulted in a change of Ileu360Asn that might generate an additional glycosylation site. In the third patient an A1285G transition was revealed. This mutation that originated de novo was localized in a region that is highly conserved in TNF ligand family and caused substitution of Ala349Thr. Localization of the mutations in the extracellular domain of ectodysplasin A suggested that the primary cause of EDA is a defect in communication between the cells responsible for the development of skin appendages. Despite a different character and localization of the mutations, no apparent correlation between phenotype and genotype of the patients was evidenced. Some differences in the patients' phenotype were observed.

Child↗
PubMed1996

The Drosophila genes crumbs and stardust are involved in the biogenesis of adherens junctions.

Morphogenetic movements of epithelia during development underlie the normal elaboration of the final body plan. The tissue integrity critical for these movements is conferred by anchorage of the cytoskeleton by adherens junctions, initially spot and later belt-like, zonular structures, which encircle the apical side of the cell. Loss-of-function mutations in the Drosophila genes crumbs and stardust lead to the loss of cell polarity in most ectodermally derived epithelia, followed in some, such as the epidermis, by extensive apoptosis. Here we show that both mutants fail to establish proper zonulae adherentes in the epidermis. Our results suggest that the two genes are involved in different aspects of this process. Further, they are compatible with the hypothesis that crumbs delimits the apical border, where the zonula adherens usually forms and where Crumbs protein is normally most abundant. In contrast, stardust seems to be required at an earlier stage for the assembly of the spot adherence junctions. In both mutants, the defect observed at the ultrastructural level are preceded by a misdistribution of Armadillo and DE-cadherin, the homologues of beta-catenin and E-cadherin, respectively, which are two constituents of the vertebrate adherens junctions. Strikingly, expansion of the apical membrane domain in epidermal cells by overexpression of crumbs also abolishes the formation of adherens junctions and results in the disruption of tissue integrity, but without loss of membrane polarity. This result supports the view that membrane polarity is independent of the formation of adherens junctions in epidermal cells.

Animals↗
PubMed1996

Integrin alpha 6 expression is required for early nervous system development in Xenopus laevis.

The integrin alpha 6 subunit pairs with both the beta 1 and beta 4 subunits to form a subfamily of laminin receptors. Here we report the cDNA cloning and primary sequence for the Xenopus homologue of the mammalian integrin alpha 6 subunit. We present data demonstrating the spatial and temporal expression of alpha 6 mRNA and protein during early development. Initially, alpha 6 transcripts are expressed in the dorsal ectoderm and future neural plate at the end of gastrulation. Later in development, alpha 6 mRNAs are expressed in a variety of neural derivatives, including the developing sensory placodes (otic and olfactory) and commissural neurons within the neural tube. Integrin alpha 6 is also expressed in the elongating pronephric duct as well as a subset of the rhombencephalic neural crest, which will form the Schwann cells lining several cranial nerves (VII, VIII and X). In vivo expression of an alpha 6 antisense transcript in the animal hemisphere leads to a reduction in alpha 6 protein expression, a loss of adhesion to laminin, and severe defects in normal development. In 35% of cases, reduced levels of alpha 6 expression result in embryos that complete gastrulation normally but arrest at neurulation prior to the formation of the neural plate. In an additional 22% of cases, embryos develop with severe axial defects, including complete loss of head or tail structures. In contrast, overexpression of the alpha 6 subunit by injection of full-length mRNA has no apparent effect on embryonic development. Co-injection of antisense and sense plasmid constructs results in a partial rescue of the antisense-generated phenotypes. These data indicate that the integrin alpha 6 subunit is critical for the early development of the nervous system in amphibians.

3T3 Cells↗
PubMed2000

Formation of corneal endothelium is essential for anterior segment development - a transgenic mouse model of anterior segment dysgenesis.

The anterior segment of the vertebrate eye is constructed by proper spatial development of cells derived from the surface ectoderm, which become corneal epithelium and lens, neuroectoderm (posterior iris and ciliary body) and cranial neural crest (corneal stroma, corneal endothelium and anterior iris). Although coordinated interactions between these different cell types are presumed to be essential for proper spatial positioning and differentiation, the requisite intercellular signals remain undefined. We have generated transgenic mice that express either transforming growth factor (alpha) (TGF(alpha)) or epidermal growth factor (EGF) in the ocular lens using the mouse (alpha)A-crystallin promoter. Expression of either growth factor alters the normal developmental fate of the innermost corneal mesenchymal cells so that these cells often fail to differentiate into corneal endothelial cells. Both sets of transgenic mice subsequently manifest multiple anterior segment defects, including attachment of the iris and lens to the cornea, a reduction in the thickness of the corneal epithelium, corneal opacity, and modest disorganization in the corneal stroma. Our data suggest that formation of a corneal endothelium during early ocular morphogenesis is required to prevent attachment of the lens and iris to the corneal stroma, therefore permitting the normal formation of the anterior segment.

Animals↗
PubMed1986

Aplasia cutis congenita: a clinical review and proposal for classification.

Aplasia cutis congenita is a condition in which localized or widespread areas of skin are absent at birth. Several distinct clinical subtypes occur, characterized by the location and pattern of skin absence, the presence of associated malformations, and the mode of inheritance. The disorder is seen most frequently on the scalp, often as a solitary lesion without other anomalies. Scalp lesions can be seen in association with limb reduction defects and in association with epidermal and organoid nevi. Lesions may overlie overt or occult embryologic malformations. A form of aplasia cutis congenita occurs in association with placental infarcts or the in utero death of a twin fetus. The condition may be associated with epidermolysis bullosa, specific teratogens or intrauterine infections, or it may occur in the presence of chromosomal abnormalities, ectodermal dysplasias, or other syndromes of malformation. A classification for aplasia cutis congenita is proposed.

Abnormalities, Drug-Induced↗
PubMed1995

Distribution of p21ras during primary palate formation of non-cleft and cleft strains of mice.

Cleft lip, with or without cleft palate, is one of the most common defects in craniofacial formation. The primary palatogenesis of mice is similar to that of humans and spontaneous cleft lip is associated with genotype in both mice and humans. To investigate the temporal and spatial expression of ras genes in cleft (A/WySn) and non-cleft strains of mice (BALB/cBy), a broad spectrum ras antibody was used. Positive staining was found in ectodermal, mesenchymal, and neuroepithelial cells of facial prominences before the primary palate formation stage (10 d 20 hr) in both strains. During the primary palate formation stage (11 d 20 hr), positive staining was found in the ectodermal and mesenchymal cells of the facial prominences of the non-cleft strain but not in those of the cleft strain. These results suggest ras genes may play a role in the primary palatogenesis of mice. Cleft lip could be associated with the deficiency of ras gene expression during primary palate formation of mice.

Animals↗
PubMed2006

Foxe3 is required for morphogenesis and differentiation of the anterior segment of the eye and is sensitive to Pax6 gene dosage.

The dysgenetic lens (dyl) mouse mutant has mutations in Foxe3, which inactivate DNA binding by the encoded forkhead transcription factor. Here we confirm, by targeted inactivation, that Foxe3 mutations are responsible for the dyl phenotype, which include loss of lens epithelium; a small, cataractic lens; and failure of the lens to detach from the surface ectoderm. In contrast to a recent report of targeted Foxe3, we found no phenotypic difference between dyl and Foxe3(-/-) mutants when congenic strains were compared, and thus nothing that argues against Foxe3(dyl) being a null allele. In addition to the lens, most tissues of the anterior segment-iris, cornea, ciliary body and trabecular meshwork-are malformed or show differentiation defects. Many of these abnormalities, such as irido-corneal and irido-lenticular adherences, are present in a less severe form in mice heterozygous for the Foxe3 mutation, in spite of these having an intact lens epithelium. Early Foxe3 expression is highly sensitive to a halved Pax6 gene dosage and there is a striking phenotypic similarity between Pax6 and Foxe3 mutants. We therefore propose that many of the ocular malformations associated with Pax6 haploinsufficiency are consequences of a reduced expression of Foxe3.

Animals↗
PubMed1978

Prevalence of growth hormone deficiency in children with cleft lip or palate.

Two hundred children 7 to 14 years of age with isolated cleft defects of the lip, palate, or both were surveyed for stature. Twelve percent were less than the third percentile in height and were designated "short." All of the short children received an endocrine evaluation. Endogenous growth hormone was examined after two days' pretreatment with stilbesteral. Four of the 25 short children with CLP had total, and four had partial, GH deficiency. Three of the GH-deficient patients were also deficient in ACTH or TSH. In contrast, in a series of 75 short (less than third percentile) children 7 to 14 years of age without cleft defect or other apparent congenital abnormality, only two had total and two had partial GH deficiency. The data suggest that children with isolated CLP have short stature about four times more often, and GH-deficiency about 40 times more often, than children without CLP. The increased prevalence of GH-deficiency may stem from the embryologic relation of adenohypophysis and oral ectoderm.

Adolescent↗
PubMed2006

Function of the two Xenopus smad4s in early frog development.

Signals from the transforming growth factor beta family members are transmitted in the cell through specific receptor-activated Smads and a common partner Smad4. Two Smad4 genes (alpha and beta/10, or smad4 and smad4.2) have been isolated from Xenopus, and conflicting data are reported for Smad4beta/10 actions in mesodermal and neural induction. To further understand the functions of the Smad4s in early frog development, we analyzed their activities in detail. We report that Smad10 is a mutant form of Smad4beta that harbors a missense mutation of a conserved arginine to histidine in the MH1 domain. The mutation results in enhanced association of Smad10 with the nuclear transcription corepressor Ski and leads to its neural inducing activity through inhibition of bone morphogenetic protein (BMP) signaling. In contrast to Smad10, both Smad4alpha and Smad4beta enhanced BMP signals in ectodermal explants. Using antisense morpholino oligonucleotides (MOs) to knockdown endogenous Smad4 protein levels, we discovered that Smad4beta was required for both activin- and BMP-mediated mesodermal induction in animal caps, whereas Smad4alpha affected only the BMP signals. Neither Smad4 was involved directly in neural induction. Expression of Smad4beta-MO in early frog embryos resulted in reduction of mesodermal markers and defects in axial structures, which were rescued by either Smad4alpha or Smad4beta. Smad4alpha-MO induced only minor deficiency at late stages. As Smad4beta, but not Smad4alpha, is expressed at high levels maternally and during early gastrulation, our data suggest that although Smad4alpha and Smad4beta may have similar activities, they are differentially utilized during frog embryogenesis, with only Smad4beta being essential for mesoderm induction.

Activins↗
PubMed2002

The Xenopus receptor tyrosine kinase Xror2 modulates morphogenetic movements of the axial mesoderm and neuroectoderm via Wnt signaling.

The Spemann organizer plays a central role in neural induction, patterning of the neuroectoderm and mesoderm, and morphogenetic movements during early embryogenesis. By seeking genes whose expression is activated by the organizer-specific LIM homeobox gene Xlim-1 in Xenopus animal caps, we isolated the receptor tyrosine kinase Xror2. Xror2 is expressed initially in the dorsal marginal zone, then in the notochord and the neuroectoderm posterior to the midbrain-hindbrain boundary. mRNA injection experiments revealed that overexpression of Xror2 inhibits convergent extension of the dorsal mesoderm and neuroectoderm in whole embryos, as well as the elongation of animal caps treated with activin, whereas it does not appear to affect cell differentiation of neural tissue and notochord. Interestingly, mutant constructs in which the kinase domain was point-mutated or deleted (named Xror2-TM) also inhibited convergent extension, and did not counteract the wild-type, suggesting that the ectodomain of Xror2 per se has activities that may be modulated by the intracellular domain. In relation to Wnt signaling for planar cell polarity, we observed: (1) the Frizzled-like domain in the ectodomain is required for the activity of wild-type Xror2 and Xror2-TM; (2) co-expression of Xror2 with Xwnt11, Xfz7, or both, synergistically inhibits convergent extension in embryos; (3) inhibition of elongation by Xror2 in activin-treated animal caps is reversed by co-expression of a dominant negative form of Cdc42 that has been suggested to mediate the planar cell polarity pathway of Wnt; and (4) the ectodomain of Xror2 interacts with Xwnts in co-immunoprecipitation experiments. These results suggest that Xror2 cooperates with Wnts to regulate convergent extension of the axial mesoderm and neuroectoderm by modulating the planar cell polarity pathway of Wnt.

Amino Acid Sequence↗
PubMed1988

Hypohidrotic ectodermal dysplasia: a genealogic, stereomicroscope, and scanning electron microscope study.

This is a report of three patients with hypohidrotic ectodermal dysplasia, or Christ-Siemens-Touraine syndrome, their genealogic backgrounds and the stereomicroscope and scanning electron microscopic appearances of the hair, the skin of their fingertips and palms as well as skin studies of members of their families. The skin morphology was recorded by means of silicone monomer rubber impressions and epoxy resin dyes. In two of the patients the disease was acquired by X-linked inheritance, while in the third, a boy, it appeared to follow an autosomal dominant pattern. Defects of the skin of the fingertips and palms of the propositi and members of the families included abnormalities of the morphology and pattern of the epidermal ridges, reduction of sweat pores varying from 13 to 87% of normal, and changed anatomy of the openings of the sweat glands. The openings were shallow and with less whorling compared to the normal, funnel-shaped sweat pores. Among the sweat pores, micropores, or openings with an average diameter of 5.3 micrometers, were observed. One of the propositi and the affected father of another had orifices on their fingertips resembling hair sheaths. Two propositi and the affected father of one exhibited grooving of the hair. The findings confirm the necessity for genealogic investigations in patients with or suspected of having the disease in order to advise parents or prospective parents. They also illustrate the usefulness of stereomicroscopy and scanning electron microscopy in observing skin and hair abnormalities.

Child↗
PubMed1998

Non-cell autonomous induction of apoptosis and loss of posterior structures by activation domain-specific interactions of Oct-1 in the Xenopus embryo.

Oct-1, a member of the POU family of transcription factors, is expressed at relatively high levels in ectodermal and mesodermal cell lineages during early Xenopus embryogenesis (Veenstra et al, 1995). Here we show that overexpression of Oct-1 induces programmed cell death concomitant with the loss of the posterior part of the body axis. Truncated Oct-1 variants, missing either the C-terminal or N-terminal trans-activation domain, exhibit a different capacity to cause such developmental defects. Oct-1-induced cell death is rescued in unilaterally injected embryos by non-injected cells, indicative of the non-cell autonomous character of the developmental effects of Oct-1. This was confirmed by marker gene analysis, which showed a significant decrease in brachyury expression, suggesting that Oct-1 interferes with an FGF-type signalling pathway.

Animals↗