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PubMed2002

An Fgf8 mouse mutant phenocopies human 22q11 deletion syndrome.

Deletion of chromosome 22q11, the most common microdeletion detected in humans, is associated with a life-threatening array of birth defects. Although 90% of affected individuals share the same three megabase deletion, their phenotype is highly variable and includes craniofacial and cardiovascular anomalies, hypoplasia or aplasia of the thymus with associated deficiency of T cells, hypocalcemia with hypoplasia or aplasia of the parathyroids, and a variety of central nervous system abnormalities. Because ablation of neural crest in chicks produces many features of the deletion 22q11 syndrome, it has been proposed that haploinsufficiency in this region impacts neural crest function during cardiac and pharyngeal arch development. Few factors required for migration, survival, proliferation and subsequent differentiation of pharyngeal arch neural crest and mesoderm-derived mesenchyme into their respective cardiovascular, musculoskeletal, and glandular derivatives have been identified. However, the importance of epithelial-mesenchymal interactions and pharyngeal endoderm function is becoming increasingly clear. Fibroblast growth factor 8 is a signaling molecule expressed in the ectoderm and endoderm of the developing pharyngeal arches and known to play an important role in survival and patterning of first arch tissues. We demonstrate a dosage-sensitive requirement for FGF8 during development of pharyngeal arch, pharyngeal pouch and neural crest-derived tissues. We show that FGF8 deficient embryos have lethal malformations of the cardiac outflow tract, great vessels and heart due, at least in part, to failure to form the fourth pharyngeal arch arteries, altered expression of Fgf10 in the pharyngeal mesenchyme, and abnormal apoptosis in pharyngeal and cardiac neural crest. The Fgf8 mutants described herein display the complete array of cardiovascular, glandular and craniofacial phenotypes seen in human deletion 22q11 syndromes. This represents the first single gene disruption outside the typically deleted region of human chromosome 22 to fully recapitulate the deletion 22q11 phenotype. FGF8 may operate directly in molecular pathways affected by deletions in 22q11 or function in parallel pathways required for normal development of pharyngeal arch and neural crest-derived tissues. In either case, Fgf8 may function as a modifier of the 22q11 deletion and contribute to the phenotypic variability of this syndrome.

Abnormalities, Multiple↗
PubMed2006

Intracranial neurenteric cyst with recurrence and extensive craniospinal dissemination.

Neurenteric cyst represents a rare cystic lesion of the central nervous system, and is generally thought to result from failure of separation of neuro-ectodermal and endodermal elements during week 3 of embryogenesis. Although recurrences have been reported, only one case of craniospinal dissemination has previously been reported. We describe a unique intracranial neurenteric cyst with recurrence and dissemination to the spinal cord.

Adult↗
PubMed1997

The mesodermal expression of rolling stone (rost) is essential for myoblast fusion in Drosophila and encodes a potential transmembrane protein.

In homozygous rolling stone embryos, the fusion of myoblasts to syncytial myotubes is diminished. Nevertheless, the visceral mesoderm, the heart mesoderm, and few somatic muscles are properly formed. Thus, we postulate a central role of rolling stone for the fusion process within the somatic mesoderm. We have cloned the rolling stone gene, and the deduced protein sequence is in accordance with a transmembrane protein, which agrees with the enrichment of Rost in the membrane fraction of Drosophila embryos. No homologous genes have been described so far. rolling stone is expressed in the embryonic nervous system and cells of the somatic mesoderm, most notable in muscle founder cells. To elucidate the function of rolling stone for myoblast fusion, we applied a knock-out strategy. The expression of an antisense rolling stone transcript specifically within the mesoderm of wild-type embryos results in fusion defects of myoblasts, proving that the rolling stone expression in the mesoderm is responsible for the rolling stone phenotype. We suggest that rolling stone is a member of a group of genes that are necessary for the fusion process during myogenesis.

Amino Acid Sequence↗
PubMed1995

Extensive symmetric truncal aplasia cutis congenita without fetus papyraceus or macroscopic evidence of placental abnormalities.

Aplasia cutis congenita is a rare disorder characterized by localized absence of skin at birth. Type V in Frieden's classification, which is associated with fetus papyraceous or placental infarcts, occurs as a large cutaneous defect on the trunk and extremities. The patient we report had a lesion affecting the trunk and extremities symmetrically, with no family history of the disorder or chromosomal abnormalities. In our opinion, despite the absence of fetus papyraceous or placental infarct, this patient's condition can be classified as type V.

Ectodermal Dysplasia↗
PubMedDate not supplied

Aplasia cutis congenita: report of one case.

We present a female newborn with a skin defect on the vertex. Aplasia cutis congenita was diagnosed. No associated anomaly was found. There was no family or drug history noted. At one-year follow-up, the lesion tended to contract and became epithelialized. We report this case and also review the literature, and then we suggest a checklist for aplasia cutis congenita.

Ectodermal Dysplasia↗
PubMed2003

Bmp4 gene is expressed at the putative site of fusion in the midfacial region.

The molecular mechanisms by which the primordia of the midface grow and fuse to form the primary palate portion of the craniofacial region are not well characterized. This is in spite of the fact that failure of growth and/or fusion of these primordia leads to the most common craniofacial birth defect in humans (i.e. clefts of the lip and/or palate). Bmp4 plays a critical role during early embryonic development and has previously been shown to play a role in epithelial-mesenchymal interactions in the craniofacial region of chicks. We analyze the expression of bmp4 in mouse as the midfacial processes undergo fusion to form the primary palate. We show that bmp4 is expressed in a very distinct manner in the three midfacial processes (lateral nasal, LNP, medial nasal, MNP, and maxillary processes, MxP) that ultimately fuse to form the midface. Prior to fusion of the midfacial processes, bmp4 is expressed in the ectoderm of the LNP, MNP, and MxP in a distinct spatial and temporal manner near and at the site of fusion of the midface. Bmp4 appears to demarcate the cells in the LNP and MNP that will eventually contact and fuse with each other. As fusion of the three prominences proceeds, some bmp4 expressing cells are trapped in the fusion line. Later, the expression of bmp4 switches to the mesenchyme of the midface underlying its initial expression in the ectoderm. The switch occurs soon after fusion of the three processes. The pattern of expression in the midfacial region implicates the important role of bmp4 in mediating the fusion process, possibly through apoptosis of cells in the putative site of fusion, during midfacial morphogenesis.

Animals↗
PubMed2003

Johnson-McMillin syndrome, a neuroectodermal syndrome with conductive hearing loss and microtia: report of a new case.

In 1983, Johnson et al. described 16 related individuals with alopecia, anosmia or hyposmia, conductive hearing loss, microtia and/or atresia of the external auditory canal, and hypogonadotrophic hypogonadism inherited in an autosomal dominant pattern. Other less constant manifestations included facial asymmetry, mental retardation, congenital heart defect, cleft palate, and choanal stenosis. An isolated case was reported later (Johnston et al. [1987: Am J Med Genet 26: 925-927]) and thereafter an affected mother and son (Hennekam and Holtus [1993: Am J Med Genet 47: 714-716]). We describe an additional unrelated female patient with features resembling those of the previously reported cases. She presented with intrauterine growth deficiency, microcephaly, alopecia, bilateral microtia with canal atresia, conductive hearing loss, partial left facial palsy, posterior cleft palate, left choanal stenosis, tetralogy of Fallot, developmental delay, and right thumb polydactyly. Because the phenotypic abnormalities in this syndrome affect the brain, facial structures, ectoderm and its derivatives, outflow tract of the heart, and Rathke's pouch derivatives, this has suggested to previous authors etiologic involvement of the ectoderm and neuroectoderm of the first and second branchial arches, Rathke's pouch, and the diencephalon. Microtia with conductive hearing loss differentiates the condition from other ectodermal dysplasias. In the initial report, females appeared somewhat less affected than males, and there was male-to-male transmission. The mother of our patient manifests subtle features, which suggest she may be a mildly affected female. Additionally, there is a family history of early-onset alopecia in the maternal grandfather's relatives.

Abnormalities, Multiple↗
PubMed2000

Coccygeal pits.

BACKGROUND: Congenital dermal sinuses represent cutaneous depressions or tracts that are lined by stratified squamous epithelium. They communicate between the surface of the skin and deeper structures and may occur anywhere along the craniospinal axis. These sinuses are thought to result from abnormal separation of the cutaneous and neural ectoderm between the third and fifth week of intrauterine life. They may be often accompanied by other cutaneous stigmata, various dysraphic abnormalities, or intraspinal tumors. In the sacrococcygeal area, cutaneous congenital abnormalities are relatively common. It is estimated that 2% to 4% of children harbor intergluteal dorsal dermal sinuses. These intergluteal sinuses in the perianal region are frequently referred to as pits or dimples. Their cause is considered similar to other congenital dermal sinuses and appears unrelated to acquired pilonidal conditions observed in adults. They may become susceptible to local recurrent infection from trauma or hirsutism. Controversy regarding the evaluation and management of cutaneous defects in the coccygeal region exists. METHODS: Both a literature review and a career review of clinical material were performed. Databases for articles published in English were surveyed for key words relating to coccygeal sinuses using standard computerized search techniques. The medical records of children presenting to our neurosurgical clinic for evaluation of dorsal dermal sinuses were reviewed to identify those with intergluteal sinuses. RESULTS: In the evaluation of reported cases and of our own, we were unable to identify any children with coccygeal sinuses without other cutaneous markers other than hair with findings suggestive of intraspinal communication. CONCLUSIONS: Intergluteal dorsal dermal sinuses are relatively common lesions that frequently come to neurosurgical attention. They do not seem to be associated with significant risk of spinal cord and intraspinal anomalies. Simple intergluteal dorsal dermal sinuses without other cutaneous findings do not require radiographic or surgical evaluation and treatment. If other markers or neurologic symptoms are present, however, radiographic evaluation may be indicated.

Buttocks↗
PubMed1998

A key function for alphav containing integrins in mesodermal cell migration during Pleurodeles waltl gastrulation.

During cleavage of Pleurodeles waltl amphibian embryos, inner cells of the blastocoel roof (presumptive ectodermal and mesodermal cells) organize a fibrillar extracellular matrix (ECM) containing fibronectin on their basal surface by a beta1-integrin-dependent process. This matrix is used as a migratory substrate by mesodermal cells during gastrulation. While alpha5beta1 integrin is expressed on both ectodermal and mesodermal cell surface, we have shown previously that alphav containing integrins are essentially restricted to the surface of mesodermal cells (Alfandari, D., Whittaker, C. A., DeSimone, D. W., and Darribère, T., Dev. Biol. 170, 249-261, 1995). To investigate the function of alphav integrins during gastrulation, we have generated a function blocking antibody directed against the extracellular domain of the Pleurodeles integrin alphav subunit. The antibody did not prevent fibronectin fibril formation, whereas an antibody against the alpha5beta1 integrin did. When injected into the blastocoel, the antibody against integrin alphav subunit perturbed gastrulation and further development in a stage-dependent manner. Developmental defects were correlated to an abnormal positioning of the mesoderm layer. In vitro, the antibody blocked spreading of mesodermal cell to fibronectin or blastocoel roof ECM but not their attachment. In contrast, the antibody directed against the alpha5beta1 integrin inhibited both cell attachment and spreading to the same substrates. We propose that the alpha5beta1 integrin is required for fibronectin assembly into fibrils and mesodermal cell attachment to the blastocoel roof ECM, while the alphav containing integrins are necessary for cell spreading, and possibly migration, on this complex network.

Animals↗
PubMed2003

Encephalotrigeminal angiomatosis.

We report an unusual case of encephalotrigeminal angiomatosis in which the facial and oral angioma was bilateral, and several teeth were congenitally absent. The developmental nature of the anomaly is reviewed. Encephalotrigeminal angiomatosis is commonly referred to as the Sturge-Weber syndrome, after Sturge and Weber who first described this affliction in 1879. The main clinical features of this syndrome are 1. venous angiomatosis of the leptomeninges of the cerebral-cortex, usually unilaterally 2. ipsilateral facial angiomatosis that often follows in outline the distribution of the trigeminal nerve (Fig 1) 3. ipsilateral gyriform calcification of the cerebral cortex 4. epileptic convulsions (contralateral focus) or other seizures 5. ocular defects (choroidal angioma, glaucoma hemianopia) 6. mental retardation 7. contralateral hemiplegia 8. obesity 9. oral mucosal and gingival involvement. Other less typical features are 1. association with hypomelanosis of 1 to 10 2. leptomeningeal angioma contralateral to the facial nevus 3. leptomeningeal angioma without facial vascular naevus 4. association with gastro intestinal hemorrhage 5. paranasal sinus enlargement. This syndrome that affects males and females equally, is a rare congenital disorder, apparently hamartomatous in nature, from persistence of a primitive embryonal vascular plexus. During the sixth week of intra-uterine life this plexus develops around the cephalic portion of the neural tube and under the ectoderm in the region destined to become facial skin. In the Sturge-Weber syndrome, the vascular plexus fails to regress, as is normal during the ninth week, resulting in angiomatosis of the related tissues. Variation in the degree of persistence or regression of the vascular plexus accounts for unilaterality or bilaterality of involvement, and also for an incomplete syndrome in which the leptomeninges, but not the facial tissues are affected. Leptomeningeal angiomatosis is the primary abnormality of encephalotrigeminal angiomatosis, all other features of the syndrome probably being secondary to this. Calcification of the cortex is a poorly understood phenomenon which may result from stasis of blood in the angioma, associated with altered local metabolism. Epilepsy and other neurological seizures, and mental retardation are probably, in their turn, secondary to the cortical calcification. The most striking clinical feature of the Sturge-Weber syndrome is the facial vascular naevus which generally follows the distribution of innervation of one or more divisions of the trigeminal nerve, whence the term encephalotrigeminal angiomatosis. However, the naevus may be more extensive, down the neck and even onto the chest. The oral tissues underlying the affected facial tissues are invariably also angiomatous and may be considerably enlarged as a result. Alterations in eruption of teeth have also been noted. Histologically, affected soft tissues are very vascular, resembling a pyogenic granuloma or a capillary, or cavernous hemangioma. Yukna, Cassingham and Carr noted that affected bone was partially replaced by a delicate fibrous tissue containing thin-walled vascular spaces. Neither inflammatory cells, nor fatty or haemopoietic marrow was noted.

Anodontia↗
PubMed2001

The BMP antagonists Chordin and Noggin have essential but redundant roles in mouse mandibular outgrowth.

Here we investigate the roles of the Bone Morphogenetic Protein (BMP) antagonists Chordin and Noggin in development of the mandible, which is derived from the first branchial arch (BA1). Both genes are expressed in the pharynx during early mandibular outgrowth and later in the mandibular process. Mice mutant for either Nog or Chd have only mild mandibular defects; however, pups of the genotype Chd(-/-);Nog(+/-) exhibit a range of mandibular truncation phenotypes, from normal to agnathia. A few embryos homozygous null for both genes survive to late gestation; many are agnathic, though a few have significant mandibular outgrowth. In mandibular explants, ectopic BMP4 rapidly induces expression of both Chd and Nog, consistent with results obtained in vivo with mutant embryos. Previous work has shown that FGF8 is a survival factor for cells populating the mandibular bud. We find that excess BMP4 represses Fgf8 transcription in mandibular explants. Embryos lacking these BMP antagonists often show a strong reduction in Fgf8 expression in the pharyngeal ectoderm, and increased cell death in the mandibular bud. We suggest that the variable mandibular hypoplasia in double mutants involves increased BMP activity downregulating Fgf8 expression in the pharynx, decreasing cell survival during mandibular outgrowth.

Animals↗
PubMedDate not supplied

Basement membrane fragility underlies embryonic lethality in fukutin-null mice.

Fukuyama-type congenital muscular dystrophy (FCMD), associated with brain malformation due to defects in neuronal migration, is caused by mutations in fukutin. Several lines of evidence suggest that the fukutin protein plays a pivotal role in synthesis of O-mannosyl sugar moieties of alpha-dystroglycan, a cell surface laminin receptor. Here, through targeted disruption of the orthologous mouse fukutin gene, we show that the fukutin protein is essential, as homozygous-null embryos die by E9.5 of gestation. Fukutin-null embryos show phenotypic diversity, features of which include growth retardation, folding of the egg cylinder, leakage of maternal red blood cells into the yolk sac cavity, and an increased number of apoptotic cells in the ectoderm. Loss of immunoreactivity against sugar moieties in alpha-dystroglycan suggests a reduced laminin-binding capacity. Ultrastructural analysis shows thin and breached basement membranes (BMs). BM fragility may underlie all of these abnormal phenotypes, and maintenance of BM function may require fukutin-mediated glycosylation of alpha-dystroglycan early in embryonic development.

Animals↗
PubMed1998

Reticulolinear aplasia cutis congenita of the face and neck: a distinctive cutaneous manifestation in several syndromes linked to Xp22.

A distinct form of aplasia cutis congenita presenting as linear facial skin defects has been described under a variety of names as Xp deletion syndrome. MIDAS (microphthalmia, dermal aplasia and sclerocornea) syndrome, MLS (microphthalmia and linear skin defects) and Gazali-Temple syndrome. The syndrome is lethal in males, and its severity in females varies from a relatively mild residual facial scarring with short stature to lethal developmental organ malformations. A new case with peculiar ultrastructural findings is presented. A review of the literature suggests that these associations represent a series of contiguous-gene syndromes.

Chromosome Deletion↗
PubMed1998

[The Johanson-Blizzard syndrome].

A 17 year and 10 month old boy with Johanson-Blizzard syndrome is presented as a case report for the first time. Diagnosis has been established on the basis of craniofacial abnormalities: microcephalia, parietal skin and bone defects, sparse hair with frontal up sweep, alae nasi hypoplasia, irregular dentition and nasolacrimal fistula, with mental insufficiency, partial exocrine pancreatic insufficiency and low birth-weight and length, hypotonia and failure to thrive in infancy. Congenital cataract and hiatus sacralis apertus are additional signs that have never been described in the literature concerning Johanson-Blizzard syndrome.

Adolescent↗
PubMed1997

Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse.

Wnt-3a mutant embryos show defects caudal to the forelimb level; somites are absent, the notochord is disrupted, and the central nervous system has a pronounced dysmorphology. Previous studies revealed that the primary defects of the mutant embryos are likely to be in the process of paraxial mesoderm formation. In this study, we analyzed the phenotype of Wnt-3a mutant embryos at early somite stages (8.0 days post coitum), when somite formation is initiated. In Wnt-3a mutants, cells which have ingressed through the primitive streak do not migrate laterally but remain under the streak and form an ectopic tubular structure. Several neural-specific molecular markers, but no paraxial mesoderm markers, are expressed in this structure, suggesting that the ectopic tube is an additional neural tube. In normal embryos, Wnt-3a is expressed in the primitive ectoderm, including the cells which are fated to give rise to the paraxial mesoderm and neurectoderm, but expression is absent in migrating mesoderm cells. These results suggest that Wnt-3a signaling may play a role in regulating paraxial mesodermal fates, at the expense of neurectodermal fates, within the primitive ectoderm of the gastrulating mouse embryo.

Animals↗
PubMed1996

Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans.

Netrins are laminin-related proteins that guide circumferential migrations on the ectoderm. To understand how netrin cues direct cell movements, we examined the expression of nematode netrin UNC-6 from embryo to adult. UNC-6 is expressed in 12 types of neuroglia and neurons, creating a hierarchy of netrin cues in the developing nervous system. Comparing gene expression pattern with in vivo phenotypes, we suggest how multiple netrin cues, each with a characteristic role, guide cells and axons during development. We also present the molecular analysis of selective loss-of-function and null alleles. The results indicate that the biological activities of netrins are mediated through distinct protein domains. Subtle mutations in domain VI can produce selective defects in both direction- and tissue-specific guidance. EGF-like module V-2 is essential for dorsal guidance activity; we infer this module is important for interactions between UNC-6 and the dorsal guidance receptor UNC-5.

Amino Acid Sequence↗
PubMed1998

The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse.

ActRIB is a type I transmembrane serine/threonine kinase receptor that has been shown to form heteromeric complexes with the type II activin receptors to mediate activin signal. To investigate the function of ActRIB in mammalian development, we generated ActRIB-deficient ES cell lines and mice by gene targeting. Analysis of the ActRIB-/- embryos showed that the epiblast and the extraembryonic ectoderm were disorganized, resulting in disruption and developmental arrest of the egg cylinder before gastrulation. To assess the function of ActRIB in mesoderm formation and gastrulation, chimera analysis was conducted. We found that ActRIB-/- ES cells injected into wild-type blastocysts were able to contribute to the mesoderm in chimeric embryos, suggesting that ActRIB is not required for mesoderm formation. Primitive streak formation, however, was impaired in chimeras when ActRIB-/- cells contributed highly to the epiblast. Further, chimeras generated by injection of wild-type ES cells into ActRIB-/- blastocysts formed relatively normal extraembryonic tissues, but the embryo proper developed poorly probably resulting from severe gastrulation defect. These results provide genetic evidence that ActRIB functions in both epiblast and extraembryonic cells to mediate signals that are required for egg cylinder organization and gastrulation.

Activin Receptors, Type I↗
PubMed2003

Prickle 1 regulates cell movements during gastrulation and neuronal migration in zebrafish.

During vertebrate gastrulation, mesodermal and ectodermal cells undergo convergent extension, a process characterised by prominent cellular rearrangements in which polarised cells intercalate along the medio-lateral axis leading to elongation of the antero-posterior axis. Recently, it has become evident that a noncanonical Wnt/Frizzled (Fz)/Dishevelled (Dsh) signalling pathway, which is related to the planar-cell-polarity (PCP) pathway in flies, regulates convergent extension during vertebrate gastrulation. Here we isolate and functionally characterise a zebrafish homologue of Drosophila prickle (pk), a gene that is implicated in the regulation of PCP. Zebrafish pk1 is expressed maternally and in moving mesodermal precursors. Abrogation of Pk1 function by morpholino oligonucleotides leads to defective convergent extension movements, enhances the silberblick (slb)/wnt11 and pipetail (Ppt)/wnt5 phenotypes and suppresses the ability of Wnt11 to rescue the slb phenotype. Gain-of-function of Pk1 also inhibits convergent extension movements and enhances the slb phenotype, most likely caused by the ability of Pk1 to block the Fz7-dependent membrane localisation of Dsh by downregulating levels of Dsh protein. Furthermore, we show that pk1 interacts genetically with trilobite (tri)/strabismus to mediate the caudally directed migration of cranial motor neurons and convergent extension. These results indicate that, during zebrafish gastrulation Pk1 acts, in part, through interaction with the noncanonical Wnt11/Wnt5 pathway to regulate convergent extension cell movements, but is unlikely to simply be a linear component of this pathway. In addition, Pk1 interacts with Tri to mediate posterior migration of branchiomotor neurons, probably independent of the noncanonical Wnt pathway.

Animals↗