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PubMed1994

Ectopic decapentaplegic in the Drosophila midgut alters the expression of five homeotic genes, dpp, and wingless, causing specific morphological defects.

The patterns of homeotic gene expression in the Drosophila midgut visceral mesoderm are instrumental in several morphogenetic events, including the formation of the gastric caeca and the positioning of the three midgut constrictions. We demonstrate that a potent regulator of homeotic gene expression in the visceral mesoderm is the secreted growth factor-like molecule encoded by the decapentaplegic (dpp) gene. Ectopic dpp in the visceral mesoderm caused changes in the gene expression of Sex combs reduced, Antennapedia, Ultrabithorax (Ubx), and abdominal-A (abd-A) and disrupted the formation of the gastric caeca and the first and third midgut constrictions. Ectopic dpp also induced expression of teashirt, wingless (wg) and the endogenous dpp gene in the visceral mesoderm and enhanced labial expression in the adjacent endoderm. The patterns of gene expression and the formation of the second midgut constriction in the presence of ectopic dpp are most consistent with a dpp-induced transformation of virtually the entire midgut to cell fates normally seen only in the parasegment (ps)7 and ps8 regions of the midgut. We conclude that dpp is a primary signal in maintaining Ubx expression in the visceral mesoderm in a pattern different from Ubx expression in the embryonic ectoderm and in providing a cell-cell communication mechanism by which Ubx expression influences gene expression across germlayers and across the ps7 to ps8 parasegment boundary in the visceral mesoderm.

Animals↗
PubMed2004

Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome.

The hyper immunoglobulin M (IgM) syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, and defective class switch recombination and somatic hypermutation, is a heterogenous disorder with at least 5 distinct molecular defects, including mutations of the genes coding for the CD40 ligand (CD40L) and IKK-gamma (NEMO) genes, both X-linked; and mutations of CD40, activation-induced cytidine deaminase (AICDA), and uracil-DNA glycosylase (UNG), associated with autosomal recessive HIGM syndromes. To investigate the molecular basis of HIGM, we determined the prevalence of mutations affecting these 5 genes in a cohort of 140 patients (130 males and 10 females). Those patients without a molecular diagnosis were subsequently evaluated for mutations of the following genes: inducible CO-stimulator molecule (ICOS), ICOS ligand (ICOSL), and if male, Bruton tyrosine kinase (Btk) and SLAM-associated protein (SAP/SH2D1A). We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1 female); UNG in one adult male; and Btk in 3 boys. Of the remaining 25 males, one infant with hypohidrotic ectodermal dysplasia had a mutation of NEMO. None of the remaining 33 patients (24 males/9 females) had mutations affecting CD40, ICOS, ICOSL, or SH2D1, and are best classified as common variable immune deficiency (CVID), although other genes, including some not yet identified, may be responsible.

Adult↗
PubMed1980

The IVIC syndrome: a new autosomal dominant complex pleiotropic syndrome with radial ray hypoplasia, hearing impairment, external ophthalmoplegia, and thrombocytopenia.

The IVIC syndrome is an autosomal dominant condition affecting mainly the upper limbs. It is described from 19 living members of one family of mostly Caucasoid descent; it came to Venezuela from the Canary Islands 140 years ago. The new mutation appeared six generations ago. It has complete penetrance and wide expressivity for a radial ray defect which may vary from an almost normal thumb to a severely malformed upper limb. When present, the thumb has a long/slender metacarpal and a short distal phalanx, reflected in a typical metacarpophalangeal (MP) pattern profile. Anthropometry reveals delayed growth in the forearms, clavicles, and cranium during adolescence, and permanently in the spine; the maturation of the face, tibiae, and feet is normal. The radial carpal bones are always affected, some being still hypoplastic at advanced ages. Constant palmar dermatoglyphic anomalies are a high a-b ridge count, a distally placed or absent t triradius, and an increased frequency of patterns in the second interdigital area. Extraocular muscles are involved almost always, producing strabismus. Hearing is bilaterally impaired due to a mixed congenital loss, either total or partial. Mild thrombocytopenia and leukocytosis are present before the age of 50 years. There is neither associated ectodermal dysplasia nor heart involvement [except for occasional mild, incomplete right bundle branch block (IRBBB)]; imperforate anus occurs in about 10% of affected persons. The possible pathogenetic relationship to the thalidomide embryopathy and to the Holt-Oram syndrome, among others, is discussed.

Adolescent↗
PubMed1999

Fgfr2 is required for limb outgrowth and lung-branching morphogenesis.

The aim of this study was to clarify the role of Fgfr2 during later stages of embryonic development. Of two previously reported gene-targeting experiments, the more extensive Fgfr2 deletion was lethal shortly after implantation, because of trophoblast defects, whereas the less extensive one survived until midgestation with placental insufficiency and defective limb outgrowth [Xu, X., Weinstein, M., Li, C., Naski, M., Cohen, R. I., Ornitz, D. M., Leder, P. & Deng, C. (1998) Development (Cambridge, U.K.) 125, 753-765]. Fgfr2 in the early embryo is expressed in the trophectoderm, and this extra-embryonic localization persists into mid- and late gestation, when Fgfr2 also is expressed in multiple developing organs. To gain insight into the later functions of Fgfr2, fusion chimeras were constructed from homozygous mutant embryonic stem cells and wild-type tetraploid embryos. This allowed survival until term and revealed that Fgfr2 is required for both limb outgrowth and branching lung morphogenesis. The use of fusion chimeras demonstrated that early lethality was indeed because of trophectoderm defects and indicated that in the embryonic cell lineages Fgfr2 activity manifests in limb and lung development. Highly similar lung and limb phenotypes were detected recently in the loss of function mutation of Fgf10, a ligand of Fgfr2. It is likely, therefore, that whereas during early development Fgfr2 interacts with Fgf4, in limb and lung development interactions between Fgf10 and Fgfr2 may be required. Possible epithelial-mesenchymal interactions between the splicing alternatives of Fgfr2 and their specific ligands will be discussed.

Alternative Splicing↗
PubMed1994

Regulation of the dorsal morphogen by the Toll and torso signaling pathways: a receptor tyrosine kinase selectively masks transcriptional repression.

The dorsal (dl) nuclear gradient initiates the differentiation of the mesoderm, neuroectoderm, and dorsal ectoderm by activating and repressing gene expression in the early Drosophila embryo. This gradient is organized by a Toll signaling pathway that shares many common features with the mammalian IL-1 cytokine pathway. Here we present evidence that a second signaling pathway, controlled by the torso (tor) receptor tyrosine kinase, also modulates dl activity. Evidence is presented that the tor pathway selectively masks the ability of dl to repress gene expression but has only a slight effect on activation. Intracellular kinases that are thought to function downstream of tor, such as D-raf and the rolled MAP kinase, mediate this selective block in repression. Normally, the Toll and tor pathways are both active only at the embryonic poles, and consequently, target genes (zen and dpp) that are repressed in middle body regions are expressed at these sites. Constitutive activation of the tor pathway causes severe embryonic defects, including disruptions in gastrulation and mesoderm differentiation, as a result of misregulation of dl target genes. These results suggest that RTK signaling pathways can control gene expression by antirepression, and that multiple pathways can fine-tune the activities of a single transcription factor.

Animals↗
PubMed1999

The role of sonic hedgehog in normal and abnormal craniofacial morphogenesis.

There is growing evidence that implicates a role for Sonic hedgehog (SHH) in morphogenesis of the craniofacial complex. Mutations in human and murine SHH cause midline patterning defects that are manifested in the head as holoprosencephaly and cyclopia. In addition, teratogens such as jervine, which inhibit the response of tissues to SHH, also produce cyclopia. Thus, the loss of SHH signaling during early stages of neural plate patterning has a profound influence of craniofacial morphogenesis. However, the severity of these defects precludes analyses of SHH function during later stages of craniofacial development. We have used an embryonic chick system to study the role of SHH during these later stages of craniofacial development. Using a combination of surgical and molecular experiments, we show here that SHH is essential for morphogenesis of the frontonasal and maxillary processes (FNP and MXPs), which give rise to the mid- and upper face. Transient loss of SHH signaling in the embryonic face inhibits growth of the primordia and results in defects analogous to hypotelorism and cleft lip/palate, characteristics of the mild forms of holoprosencephaly. In contrast, excess SHH leads to a mediolateral widening of the FNP and a widening between the eyes, a condition known as hypertelorism. In severe cases, this widening is accompanied by facial duplications. Collectively, these experiments demonstrate that SHH has multiple and profound effects on the entire spectrum of craniofacial development, and perturbations in SHH signaling are likely to underlie a number of human craniofacial anomalies.

Animals↗
PubMed2000

Reconstruction of aplasia cutis congenita of the trunk in a newborn infant using acellular allogenic dermal graft and cultured epithelial autografts.

Aplasia cutis congenita, a congenital condition characterized by the absence of all skin layers, occurs mostly on the scalp, but may also involve the trunk and extremities. Conservative treatment using silver sulfadiazine with daily dressing change has been recommended to avoid donor site morbidity and operative risks to the neonate who may have other congenital defects. Others have proposed early surgical intervention to prevent problems associated with delayed wound healing. In this case of a newborn, the authors used an alternative therapy to avoid delayed wound healing and multiple surgical interventions. During one operative procedure, a 130-cm2 lesion on the trunk was covered with allogeneic dermis and cultured epithelial autografts (CEAs). After 2.5 weeks and with three additional applications of CEAs at bedside, 90% of the wound had healed. At 27 months, the grafted area was smooth, and pliable with normal skin texture.

Abdomen↗
PubMed1994

Neuroectodermal transcription of the Drosophila neurogenic genes E(spl) and HLH-m5 is regulated by proneural genes.

The Enhancer of split gene complex (E(SPL)-C) of Drosophila comprises seven genes encoding bHLH proteins, which are required by neuroectodermal cells for epidermal development. Using promoter and gene fusions with the lacZ gene, we determined the location of cis-acting sequences necessary for normal expression of two of the genes of the E(SPL)-C, E(spl) and HLH-m5. About 0.46 kb of E(spl) and 1.9 kb of HLH-m5 upstream sequences are necessary to reproduce the normal transcription pattern of these genes. The gene products of achaete, scute and lethal of scute, together with that of ventral nervous system condensation defective, act synergistically to specify the neuroectodermal E(spl) and HLH-m5 expression domains. Negative cross- and autoregulatory interactions of the E(SPL)-C on E(spl) contribute, directly or indirectly, to this regulation. Interactions involve DNA binding, since mutagenesis of binding sites for bHLH proteins in the E(spl) promoter abolishes neuroectodermal expression and activates ectopic expression in neuroblasts. A model for activation and repression of E(spl) in the neuroectoderm and neuroblasts, respectively, is proposed.

Animals↗
PubMed1983

Effects of maternal diabetes on early embryogenesis. Alterations in morphogenesis produced by the ketone body, B-hydroxybutyrate.

The present study used the whole embryo culture technique to determine the effects of the ketone body, B-hydroxybutyrate (B-OHB), on organogenesis in mouse embryos. Embryos of two stages (3-4 and 5-6 somites) were exposed for 24 h to a racemic mixture of D-L B-OHB at levels of 8, 16, or 32 mM/L. An abnormal pattern of development resulted, consisting of growth reduction and inhibition or delay of neural tube closure in the cranial and/or caudal regions of the embryo. These effects were dose- and age-dependent, such that younger embryos were more frequently affected than older ones, and increasing doses produced a higher rate of malformation. Growth reduction as evidenced by embryonic protein showed similar relationships. Histologic analysis of embryos exposed to 32 mM/L B-OHB for 24 h revealed numerous cytoplasmic "vacuoles" widespread throughout the neuroepithelium, mesenchyme, and ectoderm. Ultrastructurally, these "vacuoles" proved to be mitochondria that had undergone high-amplitude swelling with a loss of matrix density and few identifiable cristae. No other consistent ultrastructural changes were noted, and the mitochondria of control tissues displayed a typical orthodox configuration. While this study does not conclusively limit the effects to the D-form of B-OHB, possible relationships exist between the ultrastructural alterations, ketone body metabolism, and abnormal morphogenesis.

3-Hydroxybutyric Acid↗
PubMed2006

Aplasia cutis congenita of the scalp: therapeutic modalities.

Agenesis of scalp is an uncommon but well-recognized clinical entity. Congenital scalp and skull defects can be either obvious or occult; over 300 cases have been reported in literature. Aplasia cutis congenita (ACC) is recognized as a heterogeneous disorder, all characterized by focal absence of the epidermis, dermis and sometimes the calvarium and/or dura. We present a case of ACC in an infant whose mother was exposed to a teratogenic drug (Methimazole--an antithyroid drug) during pregnancy. This case report is presented to highlight the steps to successful management. Definitive full thickness scalp cover at the earliest avoids secondary infection, eschar formation and exsanguination.

Ectodermal Dysplasia↗
PubMed2004

Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression.

The mouse limb deformity (ld) mutations cause limb malformations by disrupting epithelial-mesenchymal signaling between the polarizing region and the apical ectodermal ridge. Formin was proposed as the relevant gene because three of the five ld alleles disrupt its C-terminal domain. In contrast, our studies establish that the two other ld alleles directly disrupt the neighboring Gremlin gene, corroborating the requirement of this BMP antagonist for limb morphogenesis. Further doubts concerning an involvement of Formin in the ld limb phenotype are cast, as a targeted mutation removing the C-terminal Formin domain by frame shift does not affect embryogenesis. In contrast, the deletion of the corresponding genomic region reproduces the ld limb phenotype and is allelic to mutations in Gremlin. We resolve these conflicting results by identifying a cis-regulatory region within the deletion that is required for Gremlin activation in the limb bud mesenchyme. This distant cis-regulatory region within Formin is also altered by three of the ld mutations. Therefore, the ld limb bud patterning defects are not caused by disruption of Formin, but by alteration of a global control region (GCR) required for Gremlin transcription. Our studies reveal the large genomic landscape harboring this GCR, which is required for tissue-specific coexpression of two structurally and functionally unrelated genes.

Amino Acid Sequence↗
PubMed2001

Otx2 is required for visceral endoderm movement and for the restriction of posterior signals in the epiblast of the mouse embryo.

Genetic and embryological experiments have demonstrated an essential role for the visceral endoderm in the formation of the forebrain; however, the precise molecular and cellular mechanisms of this requirement are poorly understood. We have performed lineage tracing in combination with molecular marker studies to follow morphogenetic movements and cell fates before and during gastrulation in embryos mutant for the homeobox gene Otx2. Our results show, first, that Otx2 is not required for proliferation of the visceral endoderm, but is essential for anteriorly directed morphogenetic movement. Second, molecules that are normally expressed in the anterior visceral endoderm, such as Lefty1 and Mdkk1, are not expressed in Otx2 mutants. These secreted proteins have been reported to antagonise, respectively, the activities of Nodal and Wnt signals, which have a role in regulating primitive streak formation. The visceral endoderm defects of the Otx2 mutants are associated with abnormal expression of primitive streak markers in the epiblast, suggesting that anterior epiblast cells acquire primitive streak characteristics. Taken together, our data support a model whereby Otx2 functions in the anterior visceral endoderm to influence the ability of the adjacent epiblast cells to differentiate into anterior neurectoderm, indirectly, by preventing them from coming under the influence of posterior signals that regulate primitive streak formation.

Animals↗
PubMed2003

Smad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2.

Recent in vivo evidence suggests that Wnt signaling plays a central role in determining the fate of stem cells in the ectoderm and in the neural crest by modulating bone morphogenetic protein (BMP) levels, which, in turn, influence Msx gene expression. However, the molecular mechanism regulating the expression of the Msx genes as key regulators of cell fate has not been elucidated. Here we show in murine embryonic stem cells that BMP-dependent activation of Msx2 is mediated via the cooperative binding of Smad4 at two Smad binding elements and of lymphoid enhancing factor (Lef1) at two Lef1/TCF binding sites. Lef1 can synergize with Smad4 and Smad1 to activate Msx2 promoter, and this transcriptional complex is assembled on the endogenous promoter in response to BMP2. The Wnt/beta-catenin signaling pathway can activate Msx2 via the binding of Lef1 to its promoter and synergizes with BMP2 to activate Msx2 expression, possibly via enhanced recruitment of the p300/cAMP-response element-binding protein-binding protein co-factor. Interestingly, the Wnt/beta-catenin-dependent activation of Msx2 was defective in Smad4-deficient embryonic stem cells or when Smad binding elements were mutated but persisted in the presence of various BMP antagonists, indicating that Smad4 was involved in transducing the Wnt/beta-catenin signals in the absence of a BMP autocrine loop. A chromatin immunoprecipitation analysis revealed that endogenous Smad4, but not Smad1, was part of the Lef1 transcriptional complex in response to beta-catenin activation, dismissing any implication of BMP signaling in this response. We propose that Wnt signaling pathway could dictate cell fate not only by modulating BMP levels but also by directly regulating cooperatively BMP-target genes.

Animals↗
PubMed2001

A retrospective study of incontinentia pigmenti seen at the National Skin Centre, Singapore over a 10-year period.

INTRODUCTION: Incontinentia pigmenti is a rare X-linked dominant disease which affects the ectodermal tissues, usually lethal in males. MATERIALS AND METHODS: A retrospective analysis of clinical data obtained from the photographic documentation and casenotes of patients diagnosed to have incontinentia pigmenti at the National Skin Centre. The study covered the period from January 1990 to December 1999. RESULTS: Twenty-six patients were diagnosed to have incontinentia pigmenti of the Bloch-Sulzberger type; 23 (88.5%) were females and 3 (11.5%) were males. There were 20 Chinese, 3 Malay and 3 Indian patients. Most patients had cutaneous manifestations at birth or within the first week of life. Cutaneous features included vesicles, papules, verrucous plaques and splash-like hyperpigmentation along the lines of Blaschko. The cutaneous lesions were widespread in 21 (81%) and localised in 5 (19%) patients. In some cases, hypopigmented atrophic streaks (2 patients) or whorled scarring alopecia (4 patients) were seen. Extracutaneous manifestations, seen in 5 (19%) patients, included neurological, dental and ocular defects. One Malay girl had severe neurological involvement associated with ocular abnormalities. A positive family history was present in 6 (23%) patients. The 3 male patients were Chinese without any family history. CONCLUSIONS: Each stage of the disease comes with its own set of differential diagnosis, including infections e.g. herpes virus infection and other types of genodermatoses e.g. linear and whorled nevoid hypermelanosis. The phenomenon of whorled scarring alopecia, hitherto unreported in the literature, corresponded to the lines of Blaschko. In the 3 Chinese male patients, the disorder probably originated from a new mutation. X chromosome inactivation in females during early embryogenesis results in a mosaic population of cells and this explains the linear and patchy manifestations of incontinentia pigmenti.

Adolescent↗
PubMed2003

Aplasia cutis congenita of the scalp, the skull, and the dura.

A newborn baby boy presented with a full thickness defect of the scalp, skull, and dura measuring 6 x 7 cm caused by aplasia cutis congenita. Full thickness loss is extremely rare and to our knowledge this case is the twenty-first reported. It has an established mortality of up to 55%. An encephalocele forced us to do an emergency operation with a single large scalp flap based on the supratrochlear and superficial temporal arteries. After revision the child is now 9 months old and progressing well. There are several ways to treat these rare and delicate cases.

Dura Mater↗
PubMed1988

Studies of Sl/Sld in equilibrium with +/+ mouse aggregation chimaeras. I. Different distribution patterns between melanocytes and mast cells in the skin.

In spite of their different origin, both melanocytes and mast cells are deficient in the skin of mutant mice of the Sl/Sld genotype. Since the neural crest and the liver of Sl/Sld embryos contain normal precursors of melanocytes and mast cells, respectively, the deficiency is attributed to a defect in tissue environment necessary for migration and/or differentiation of precursor cells. We investigated whether the tissue environment used for differentiation of melanocytes and mast cells was identical by producing aggregation chimaeras from Sl/Sld and +/+ embryos. Chimaeric mice with apparent pigmented and nonpigmented stripes were obtained. In the nonpigmented stripes of these Sl/Sld in equilibrium with +/+ chimaeras, melanocytes were not detectable in hair follicles but were detectable in the dermis. In contrast, melanocytes were detectable neither in hair follicles nor in the dermis of nonchimaeric Sl/Sld mice. Concentrations of mast cells were comparable in the pigmented and nonpigmented stripes of Sl/Sld in equilibrium with +/+ chimaeras, but the average concentration of mast cells significantly varied in the chimaeras (from 8% to 74% of the value observed in control +/+ mice). The present result suggests that mesodermal cells that support the migration and differentiation of both melanocyte precursors and mast-cell precursors mix homogeneously in the dermis and that ectodermal cells that influence the invasion of differentiating melanocytes into hair follicles make discrete patches.

Animals↗
PubMed2006

Eye and neural defects associated with loss of GDF6.

BACKGROUND: In Xenopus the bone morphogenetic protein growth and differentiation factor 6 (GDF6) is expressed at the edge of the neural plate, and within the anterior neural plate including the eye fields. Here we address the role of GDF6 in neural and eye development by morpholino knockdown experiments. RESULTS: We show that depletion of GDF6 (BMP13) resulted in a reduction in eye size, loss of laminar structure and a reduction in differentiated neural cell types within the retina. This correlated with a reduction in staining for Smad1/5/8 phosphorylation indicating a decrease in GDF6 signalling through loss of phosphorylation of these intracellular mediators of bone morphogenetic protein (BMP) signalling. In addition, the Pax6 expression domain is reduced in size at early optic vesicle stages. Neural cell adhesion molecule (NCAM) is generally reduced in intensity along the neural tube, while in the retina and brain discreet patches of NCAM expression are also lost. GDF6 knock down resulted in an increase in cell death along the neural tube and within the retina as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining. CONCLUSION: Our data demonstrate that GDF6 has an important role in neural differentiation in the eye as well as within the central nervous system, and that GDF6 may act in some way to maintain cell survival within the ectoderm, during the normal waves of programmed cell death.

Animals↗
PubMed1980

The influence of excess vitamin A on neural tube closure in the mouse embryo.

The effect of excess vitamin A on the closure of the neural tube in mouse embryos was examined with light microscopy, transmission and scanning electronmicroscopy. The embryos were treated with the vitamin just before closure of the brain vesicles and examined during the following 24 h, a period during which under normal conditions the brain completely closes. At 18--24 h after treatment the external features of the treated specimens began to differ from those of the controls. In the treated embryos the neural walls folded laterally and became widely separated, whereas those of the controls folded dorsomedially and fused in the midline. Histologically, the first difference between treated and control embryos was noted at two hours after treatment, when large intercellular spaces appeared between the neuroepithelial cells of the treated embryos. These spaces were mainly present between the apical ends of the wedge-shaped neuroepithelial cells. This accumulation of intercellular spaces interfered with the normal morphogenetic movement of the neural walls which remained convex instead of becoming concave. This convex bending resulted in non-closure of the neural tube. In addition to the appearance of large intercellular spaces some neuroepithelial cells as well as some mesenchymal, endothelial, and surface ectoderm cells showed swelling and degeneration as a result of the vitamin A treatment. This cell degeneration probably contributes to failure of the neural tube to close due to loss of cohesion at the luminal surface and the lack of mesenchymal support needed for the elevation of the neural walls. However, the increase of intercellular spaces at the apical side of the neuroepithelium is in all probability the major cause for the failure of the neural tube to close.

Animals↗