VI. Birth defects and genetic disorders.
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Animals↗
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Distribution and function of tenascin during cranial neural crest development in the chick.
Tenascin is a glycoprotein associated with the extracellular matrix and the surface of some cell types. Here, the distribution and possible function of tenascin have been examined along the pathways followed by cranial neural crest cells. During early stages of neural crest migration, tenascin was observed in a dense matrix surrounding premigratory cranial neural crest cells. Along the neural tube, tenascin immunoreactivity was observed in a dorsoventral gradient and was also noted under the ectoderm and around the notochord. During advanced neural crest migration, tenascin immunoreactivity colocalized with and appeared to be on the surface of migrating neural crest cells. At later stages, tenascin was present around the otic vesicles, retina, lens, and in an interstitial matrix in the region of the branchial arches. At the level of the occipital somites, tenascin immunoreactivity was observed around the neural tube, notochord, dermamyotome, and on the basal surface of the ectoderm. Tenascin was also observed in an interstitial matrix within the sclerotome. At early stages of vagal neural crest migration, immunoreactivity was uniform within the sclerotome, whereas at later stages tenascin colocalized with vagal neural crest cells within the rostral half of each sclerotome. The possible function of tenascin was tested by injecting antitenascin antibodies lateral to the mesencephalic neural tube. Two predominant defects were noted in injected embryos: 1) ectopic aggregates of cranial neural crest cells external to the neural tube and sometimes located on the apical side of the ectoderm; and 2) open and deformed neural tubes. Both the distribution and results of the perturbation experiment suggest that tenascin is required for proper cranial neural crest migration.
Animals↗
The kakapo mutation affects terminal arborization and central dendritic sprouting of Drosophila motorneurons.
The lethal mutation l(2)CA4 causes specific defects in local growth of neuronal processes. We uncovered four alleles of l(2)CA4 and mapped it to bands 50A-C on the polytene chromosomes and found it to be allelic to kakapo (. Genetics. 146:275- 285). In embryos carrying our kakapo mutant alleles, motorneurons form correct nerve branches, showing that long distance growth of neuronal processes is unaffected. However, neuromuscular junctions (NMJs) fail to form normal local arbors on their target muscles and are significantly reduced in size. In agreement with this finding, antibodies against kakapo (Gregory and Brown. 1998. J. Cell Biol. 143:1271-1282) detect a specific epitope at all or most Drosophila NMJs. Within the central nervous system of kakapo mutant embryos, neuronal dendrites of the RP3 motorneuron form at correct positions, but are significantly reduced in size. At the subcellular level we demonstrate two phenotypes potentially responsible for the defects in neuronal branching: first, transmembrane proteins, which can play important roles in neuronal growth regulation, are incorrectly localized along neuronal processes. Second, microtubules play an important role in neuronal growth, and kakapo appears to be required for their organization in certain ectodermal cells: On the one hand, kakapo mutant embryos exhibit impaired microtubule organization within epidermal cells leading to detachment of muscles from the cuticle. On the other, a specific type of sensory neuron (scolopidial neurons) shows defects in microtubule organization and detaches from its support cells.
Alleles↗
YAC rescue of downless locus mutations in mice.
Mice with mutations at the downless (dl) locus have defects in hair follicle, tooth, sweat gland, preputial gland, Meibomian gland, and tail development. The dl phenotype is analogous to the human genetic disorder termed autosomal hypohidrotic (or anhidrotic) ectodermal dysplasia (HED). On the basis of the identification of two related transgenic insertional mutations in the downless gene, yeast artificial chromosomes (YACs) were identified that map to the critical region of mouse Chromosome (Chr) 10. To determine which of the YACs contain the dl gene, we generated YAC transgenic mice by mouse embryo microinjections. The 200-kb YAC B25.D9 was found to rescue all of the downless defects. In addition, the transgenic YAC rescued the dominant Sleek (Dlslk) allele. Since the sequences within the YAC are entirely deleted in one of the transgenic mutants, our results establish that Sleek encodes a dominant-negative protein whose effects can be reversed by expression of extra copies of the wild-type locus.
Alleles↗
Bullous aplasia cutis congenita.
A tense yellow vesicle was noted on the back parietal scalp of a female newborn. This proved to be a bullous variant of aplasia cutis congenita. Only 16 cases of this apparently rare disorder have been previously reported. Histologic evaluation of such lesions reveals a distinct pattern containing fibrovascular stromas, edematous stroma, or both. Identical histologic findings are found in encephaloceles and meningoceles, supporting the recently proposed hypothesis that this variant of aplasia cutis may represent the form fruste of a neural tube closure defect. This disorder should be included in the differential diagnosis of vesicobullous lesions in the neonate. Bullous aplasia cutis congenita is a rare clinical subtype of aplasia cutis congenita with distinctive histologic findings. We present a new case, and summarize the clinical and histologic findings of the 16 cases previously reported in the English-language literature. Bullous or membranous aplasia cutis congenita may represent a form fruste of a neural tube defect.
Ectodermal Dysplasia↗
Bartsocas-Papas syndrome with fusion of the lips and posterior fusion defects of the thoracic vertebrae.
Bartsocas-Papas syndrome is a rare popliteal pterygial syndrome with multiple anomalies including microcephaly, facial clefts, filiform bands, ankyloblepharon, syndactyly, and other ectodermal anomalies. Affected infants usually die perinatally. The authors present an 8-month-old female infant with manifestations of this syndrome and some additional traits including fusion of the lips, intraoral filiform bands, alopecia totalis, and posterior fusion failure of the vertebrae. The fused lips were opened by incising the fibrotic bands closing her mouth. Details of this patient and a brief review of the literature is presented.
Abnormalities, Multiple↗
Anal atresia and abdominal wall defect as unusual symptoms in EEC syndrome.
In this report we document the concurrence of a large omphalocoele and anal atresia in a female newborn with EEC syndrome (Ectodermal dysplasia-Ectrodactyly-Cleft palate). Up to now, the association anal atresia-EEC syndrome has been noted in 4 other unpublished patients indicating that anal atresia may constitute another true manifestation of this autosomal dominant syndrome with variable expression.
Anus, Imperforate↗
Split-hand/split-foot malformation is caused by mutations in the p63 gene on 3q27.
Split-hand/split-foot malformation (SHFM), a limb malformation involving the central rays of the autopod and presenting with syndactyly, median clefts of the hands and feet, and aplasia and/or hypoplasia of the phalanges, metacarpals, and metatarsals, is phenotypically analogous to the naturally occurring murine Dactylaplasia mutant (Dac). Results of recent studies have shown that, in heterozygous Dac embryos, the central segment of the apical ectodermal ridge (AER) degenerates, leaving the anterior and posterior segments intact; this finding suggests that localized failure of ridge maintenance activity is the fundamental developmental defect in Dac and, by inference, in SHFM. Results of gene-targeting studies have demonstrated that p63, a homologue of the cell-cycle regulator TP53, plays a critically important role in regulation of the formation and differentiation of the AER. Two missense mutations, 724A-->G, which predicts amino acid substitution K194E, and 982T-->C, which predicts amino acid substitution R280C, were identified in exons 5 and 7, respectively, of the p63 gene in two families with SHFM. Two additional mutations (279R-->H and 304R-->Q) were identified in families with EEC (ectrodactyly, ectodermal dysplasia, and facial cleft) syndrome. All four mutations are found in exons that fall within the DNA-binding domain of p63. The two amino acids mutated in the families with SHFM appear to be primarily involved in maintenance of the overall structure of the domain, in contrast to the p63 mutations responsible for EEC syndrome, which reside in amino acid residues that directly interact with the DNA.
Amino Acid Sequence↗
The modifier of variegation modulo gene acts downstream of dorsoventral and HOM-C genes and is required for morphogenesis in Drosophila.
Growing evidence involves chromatin structural flexibility in gene regulation during development. modulo is a dominant suppressor of position effect variegation, suggesting the participation of its product in the assembly of higher order chromatin structures. Here we report the patterns of modulo expression and regulation during embryogenesis, analyzed in correlation with phenotypical defects resulting from the amorphic mutation of the gene. Zygotic expression of modulo depends on the activity of genes which pattern the embryo along dorsoventral and anteroposterior axes and specify diversified morphogenesis, dorsal and the mesoderm-specific genes twist and snail direct modulo expression in the presumptive mesoderm. The homeotic genes Sex combs reduced and Ultrabithorax positively regulate the gene in the ectoderm of parasegment 2 and abdominal mesoderm, respectively, modulo mutants exhibit aberrant morphogenesis of tissues originating from those embryonic primordia which normally express the gene, but do not show defect in cell fate specification. We propose that down-stream of pattern-forming genes modulo controls, via chromatin structural changes, genes critical for the process of morphogenesis of several tissue types.
Animals↗
Induction of mesoderm by a viral oncogene in early Xenopus embryos.
During frog embryogenesis, mesoderm is specified in the equatorial region of the early embryo by a signal from the vegetal hemisphere. Prospective ectodermal cells dissected from the animal hemisphere can be respecified to form mesodermal tissues by recombination with vegetal tissue or by treatment with any of several polypeptide growth factors or growth factor-like molecules. Together with the discovery that several developmental mutations in Drosophila are in genes with significant homology to mammalian mitogens and oncogenes, these observations suggest that early developmental signals may use similar transduction pathways to mitogenic signals characterized in cultured mammalian cells. Whether mesoderm can be induced by activation of intracellular signal transduction pathways implicated in mitogenesis and oncogenesis has been investigated with the viral oncogene polyoma middle T. Microinjection of middle T messenger RNA into early embryos results in the respecification of isolated prospective ectodermal tissue to form characteristic mesodermal structures. Middle T in frog blastomeres appears to associate with cellular activities similar to those observed in polyoma-transformed mouse cells, and transformation-defective middle T mutants fail to induce mesoderm. These results suggest that early inductive signals and mitogenic and oncogenic stimuli may share common signal transduction pathways.
Animals↗
Gastrointestinal and renal abnormalities in cardio-facio-cutaneous syndrome.
Cardio-facio-cutaneous syndrome (CFC) is an uncommon autosomal recessive condition recently distinguished from Noonan syndrome but with more marked growth failure and ectodermal dysplasia. Abdominal symptoms are frequently described but anatomic lesions in CFC have rarely been described. We have found significant anatomic abnormalities in CFC patients including antral foveolar hyperplasia, severe constipation with fecal impaction, nephrocalcinosis and renal cysts.
Abnormalities, Multiple↗
Oral and oesophageal squamous cell carcinoma--a complication or component of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED, APS-I).
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is an autosomal recessive disease exceptionally common in Finland. It is associated with a limited T lymphocyte defect, an autoimmune response to various tissues, particularly endocrine glands. Most patients have chronic oral candidosis, which has been suggested to be carcinogenic. In Finland 92 patients have been diagnosed with APECED and 66 of them are alive. Our aim was to study the possible association of APECED with oral and oesophageal carcinoma. We evaluated the medical histories of all 92 patients for morbidity, causes of death, and known risk factors for oral cancer. We invited all current patients for a clinical examination of their oral mucosa. Six of the 92 had developed oral or oesophageal squamous cell carcinoma (SCC) by the mean age of 37 (29-44years) and four of them had died from it. The six represent 10% of the patients older than 25years. Five of the six patients had long-lasting oral candidosis. Four of the six had smoked regularly for 15years or more. One patient had been on immunosuppressive therapy for 6years following kidney transplantation when SCC in her mouth occurred. The partial T cell defect of APECED seems to favour the growth of Candida albicans and predispose to chronic mucositis and SCC. Aggressive control of oral candidosis and close follow-up of oral mucosa is a necessity in patients with APECED.
Adolescent↗
A novel gene, BENI is required for the convergent extension during Xenopus laevis gastrulation.
Activin-like signaling plays an important role in early embryogenesis. Activin A, a TGF-beta family protein, induces mesodermal/endodermal tissues in animal cap assays. In a screen for genes expressed early after treatment with activin A, we isolated a novel gene, denoted as BENI (Brachyury Expression Nuclear Inhibitor). The BENI protein has a conserved domain at the N-terminus that contains a nuclear localization signal (NLS), and two other NLSs in the C-terminal domain. BENI mRNA was localized to the animal hemisphere at the gastrula stages and to ectoderm except for neural regions at stage 17; expression persisted until the tadpole stage. The overexpression of BENI caused gastrulation defects and inhibition of elongation of activin-treated animal caps with reduction of Xbra expression. Moreover, whole-mount in situ hybridization revealed reduced expression of Xbra in BENI mRNA-injected regions of gastrula embryos. Functional knockdown of BENI using an antisense morpholino oligonucleotide also resulted in an abnormal phenotype of embryos curling to the dorsal side, and excessive elongation of activin-treated animal caps without altered expression of mesodermal markers. These results suggested that BENI expression is regulated by activin-like signaling, and that this regulation is crucial for Xbra expression.
Activins↗
Activation of Fgf-4 and HoxD gene expression by BMP-2 expressing cells in the developing chick limb.
Bone morphogenetic protein-2 (BMP-2) has been implicated in the polarizing region signalling pathway, which specifies pattern across the antero-posterior of the developing vertebrate limb. Retinoic acid and Sonic Hedgehog (SHH) can act as polarizing signals; when applied anteriorly in the limb bud, they induce mirror-image digit duplications and ectopic Bmp-2 expression in anterior mesenchyme. In addition, the two signals can activate Fgf-4 expression in anterior ridge and HoxD expression in anterior mesenchyme. We tested the role of BMP-2 in this signalling cascade by ectopically expressing human BMP-2 (hBMP-2) at the anterior margin of the early wing bud using a replication defective retroviral vector, and found that ectopic expression of Fgf-4 was induced in the anterior part of the apical ectodermal ridge, followed later by ectopic expression of Hoxd-11 and Hoxd-13 in anterior mesenchyme. This suggests that BMP-2 is involved in regulating Fgf-4 and HoxD gene expression in the normal limb bud. Ectopically expressed hBMP-2 also induced duplication of digit 2 and bifurcation of digit 3, but could not produce the mirror-image digit duplications obtained with SHH-expressing cells. These results suggest that BMP-2 may be involved primarily in maintenance of the ridge, and in the link between patterning and outgrowth of the limb bud.
Animals↗
Patterns of lectin binding during mammalian neurogenesis.
Temporospatial changes in surface carbohydrates of neuroepithelial cells were analysed by means of lectin histochemistry in normal mouse embryos subsequent to closure of the neural tube. The lectins used were concanavalin A (con A), soybean (SBA), Maclura pomifera (MPA), peanut (PNA), wheatgerm (WGA), succinylated wheatgerm (sWGA) and Limax flavus (LFA). Although labelling was obtained with all of the lectins, the most striking temporospatial differences occurred with con A which in the early embryos (9-10 somites) labelled the basal and intercellular surfaces, but not the luminal surfaces of the neuroepithelial cells, whereas in the older embryos (26-30 somites), con A showed light luminal surface labelling. A midventral wedge of cells in the floor of the neural tube in the older embryos also exhibited more intense labelling with con A, WGA, and sWGA than with the other lectins. In addition, comparisons of lectin localisation were made between the closed neural tube in normal embryos and the open neural folds in the loop-tail (Lp) mutant mouse in which the neural tube fails to close. Although similar temporospatial patterns in lectin localisation occurred as in normal embryos, the retention of lectin labelling associated with rounded putative neural crest cells that remained sequestered in the apices of the open neural folds, along with an attenuation of the luminal reaction in the older abnormal embryos, suggest that during normal mammalian development closure of the spinal neural folds may be important for the timely exit of neural crest cells as well as for eliciting changes in the luminal surfaces of the neuroepithelial cells.
Animals↗
Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice.
The Notch signaling pathway is a conserved intercellular signaling mechanism that is essential for proper embryonic development in numerous metazoan organisms. We have examined the in vivo role of the Jagged2 (Jag2) gene, which encodes a ligand for the Notch family of transmembrane receptors, by making a targeted mutation that removes a domain of the Jagged2 protein required for receptor interaction. Mice homozygous for this deletion die perinatally because of defects in craniofacial morphogenesis. The mutant homozygotes exhibit cleft palate and fusion of the tongue with the palatal shelves. The mutant mice also exhibit syndactyly (digit fusions) of the fore- and hindlimbs. The apical ectodermal ridge (AER) of the limb buds of the mutant homozygotes is hyperplastic, and we observe an expanded domain of Fgf8 expression in the AER. In the foot plates of the mutant homozygotes, both Bmp2 and Bmp7 expression and apoptotic interdigital cell death are reduced. Mutant homozygotes also display defects in thymic development, exhibiting altered thymic morphology and impaired differentiation of gamma delta lineage T cells. These results demonstrate that Notch signaling mediated by Jag2 plays an essential role during limb, craniofacial, and thymic development in mice.
Animals↗
Epithelial and ectomesenchymal role of the type I TGF-beta receptor ALK5 during facial morphogenesis and palatal fusion.
Transforming growth factor beta (TGF-beta) proteins play important roles in morphogenesis of many craniofacial tissues; however, detailed biological mechanisms of TGF-beta action, particularly in vivo, are still poorly understood. Here, we deleted the TGF-beta type I receptor gene Alk5 specifically in the embryonic ectodermal and neural crest cell lineages. Failure in signaling via this receptor, either in the epithelium or in the mesenchyme, caused severe craniofacial defects including cleft palate. Moreover, the facial phenotypes of neural crest-specific Alk5 mutants included devastating facial cleft and appeared significantly more severe than the defects seen in corresponding mutants lacking the TGF-beta type II receptor (TGFbetaRII), a prototypical binding partner of ALK5. Our data indicate that ALK5 plays unique, non-redundant cell-autonomous roles during facial development. Remarkable divergence between Tgfbr2 and Alk5 phenotypes, together with our biochemical in vitro data, imply that (1) ALK5 mediates signaling of a diverse set of ligands not limited to the three isoforms of TGF-beta, and (2) ALK5 acts also in conjunction with type II receptors other than TGFbetaRII.
Activin Receptors, Type I↗
The syndrome of aplasia cutis congenita with terminal, transverse defects of limbs.
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Abnormalities, Multiple↗