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PubMed1998

Serum response factor is essential for mesoderm formation during mouse embryogenesis.

The transcription factor serum response factor (SRF), a phylogenetically conserved nuclear protein, mediates the rapid transcriptional response to extracellular stimuli, e.g. growth and differentiation signals. DNA- protein complexes containing SRF or its homologues function as nuclear targets of the Ras/MAPK signalling network, thereby directing gene activities associated with processes as diverse as pheromone signalling, cell-cycle progression (transitions G0-G1 and G2-M), neuronal synaptic transmission and muscle cell differentiation. So far, the activity of mammalian SRF has been studied exclusively in cultured cells. To study SRF function in a multicellular organism we generated an Srf null allele in mice. SRF-deficient embryos (Srf -/-) have a severe gastrulation defect and do not develop to term. They consist of misfolded ectodermal and endodermal cell layers, do not form a primitive streak or any detectable mesodermal cells and fail to express the developmental marker genes Bra (T), Bmp-2/4 and Shh. Activation of the SRF-regulated immediate early genes Egr-1 and c-fos, as well as the alpha-Actin gene, is severely impaired. Our study identifies SRF as a new and essential regulator of mammalian mesoderm formation. We therefore suggest that in mammals Ras/MAPK signalling contributes to mesoderm induction, as is the case in amphibia.

Animals↗
PubMed2004

pyramus and thisbe: FGF genes that pattern the mesoderm of Drosophila embryos.

The Heartless (Htl) FGF receptor is required for the differentiation of a variety of mesodermal tissues in the Drosophila embryo, yet its ligand is not known. Here we identify two new FGF genes, thisbe (ths) and pyramus (pyr), which probably encode the elusive ligands for this receptor. The two genes exhibit dynamic patterns of expression in epithelial tissues adjacent to Htl-expressing mesoderm derivatives, including the neurogenic ectoderm, stomadeum, and hindgut. Embryos that lack ths+ and pyr+ exhibit defects related to those seen in htl mutants, including delayed mesodermal migration during gastrulation and a loss of cardiac tissues and hindgut musculature. The misexpression of Ths in wild-type and mutant embryos suggests that FGF signaling is required for both cell migration and the transcriptional induction of cardiac gene expression. The characterization of htl and ths regulatory DNAs indicates that high levels of the maternal Dorsal gradient directly activate htl expression, whereas low levels activate ths. It is therefore possible to describe FGF signaling and other aspects of gastrulation as a direct manifestation of discrete threshold readouts of the Dorsal gradient.

Animals↗
PubMed1998

Xenopus Smad8 acts downstream of BMP-4 to modulate its activity during vertebrate embryonic patterning.

Bone morphogenetic proteins (BMPs) participate in the development of nearly all organs and tissues. BMP signaling is mediated by specific Smad proteins, Smad1 and/or Smad5, which undergo serine phosphorylation in response to BMP-receptor activation and are then translocated to the nucleus where they modulate transcription of target genes. We have identified a distantly related member of the Xenopus Smad family, Smad8, which lacks the C-terminal SSXS phosphorylation motif present in other Smads, and which appears to function in the BMP signaling pathway. During embryonic development, the spatial pattern of expression of Smad8 mirrors that of BMP-4. We show that an intact BMP signaling pathway is required for its expression. Overexpression of Smad8 in Xenopus embryos phenocopies the effect of blocking BMP-4 signaling, leading to induction of a secondary axis on the ventral side of intact embryos and to direct neural induction in ectodermal explants. Furthermore, Smad8 can block BMP-4-mediated induction of ventral mesoderm-specific gene expression in ectodermal explants. Overexpression of Smad8 within dorsal cells, however, causes patterning defects that are distinct from those reported in BMP-4-deficient embryos, suggesting that Smad8 may interact with additional signaling pathways. Indeed, overexpression of Smad8 blocks expression of Xbra in whole animals, and partially blocks activin signaling in animal caps. In addition, Smad8 inhibits involution of mesodermal cells during gastrulation, a phenotype that is not observed following blockade of activin or BMPs in Xenopus. Together, these results are consistent with the hypothesis that Smad8 participates in a negative feedback loop in which BMP signaling induces the expression of Smad8, which then functions to negatively modulate the amplitude or duration of signaling downstream of BMPs and, possibly, downstream of other transforming growth factor-beta (TGF-beta) family ligands.

Activins↗
PubMed2004

Inherited disorders of the skin in human and mouse: from development to differentiation.

The last ten years has revealed some of the key players in the development and differentiation of the hair follicle and the epidermis in general. In this review, we discuss how our current understanding of these processes has been made possible by the elucidation of the molecular basis of human inherited diseases and mouse mutants which display defects in the hair and epidermis. For examples, the study of ectodermal dysplasias and the basal cell carcinoma predisposition disease Gorlin syndrome have allowed the determination of signalling hierarchies critical in the formation of the hair follicle. Epidermolytic diseases and hyperkeratoses have focussed attention on the importance of the programs of keratin expression, while ichthyoses provide insight in the final stage of epidermal development, cornification. Finally, the increasing range of diseases and mouse models exhibiting alopecias are revealing the critical pathways in control of the hair follicle cycle.

Alopecia↗
PubMed1979

Dysgenetic lens (dyl)--a new gene in the mouse.

A new autosomal recessive gene, dysgenetic lens (dyl), in the mouse is described. Homozygotes are fully viable and exhibit smaller eye, corneal opacity, adhesion of the iris, cataractous degeneration, and extrusion of the lens nucleus and persistent lens-epithelium attachment. Developmental failure of lens vesicle--ectoderm separation is recognized as the earliest expression of the genetic defect. Possible significance of this mutant in the understanding of Peter's anomaly is indicated.

Animals↗
PubMed2006

Unilateral retinal dysplasia--a case report.

Retinal dysplasia is an uncommon condition and may be either unilateral or bilateral. It represents disturbed differentiation of neural ectoderm. It can be sporadic or may be associated with genetic defects. A case of unilateral retinal dysplasia in a 2 year old male child is reported.

Child, Preschool↗
PubMed2005

Heritable defects of the human TLR signalling pathways.

Recently, three human primary immunodeficiencies associated with impaired TLR signalling were described. Anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID), either X-linked recessive or autosomal dominant, is caused by hypomorphic mutations in NEMO or hypermorphic mutation in IKBA, respectively, both involved in nuclear factor-kappaB (NF-kappaB) activation. These patients present with abnormal development of ectoderm-derived structures and suffer from a broad spectrum of infectious diseases. In vitro studies of the patients' cells showed an impaired, but not abolished, NF-kappaB activation in response to a large set of stimuli, including TLR agonists. More recently, patients with autosomal recessive amorphic mutations in IRAK4 have been reported, presenting no developmental defect and a more restricted spectrum of infectious diseases, mostly caused by pyogenic encapsulated bacteria, principally, but not exclusively Gram-positive. In vitro studies carried out with these patients' cells showed a specific impairment of the Toll-interleukin-1 receptor (TIR)-interleukin-1 receptor associated kinase (IRAK) signalling pathway. NF-kappaB- and mitogen activated protein kinase (MAPK) pathways are impaired in response to all TIR agonists tested. These data, therefore, suggest that TLRs play a critical role in host defence against pyogenic bacteria, but may be dispensable or redundant for immunity to most other infectious agents in humans.

Ectodermal Dysplasia↗
PubMed1989

Developmental enamel defects in primary teeth in children with cerebral palsy, mental retardation, or hearing defects: a review.

Developmental enamel defects in primary teeth have been found at least twice as frequently in children with cerebral palsy or mental retardation as in control children, and frequently also in children with sensori-neural hearing deficits. The developing tooth germ is sensitive to a range of systemic disturbances, some of which may also affect neurologic development. Because the enamel cannot recover once it is damaged, it may provide a repository of information on the timing and nature of insults potentially affecting other ectodermally derived structures, including the brain. This paper reviews the literature on developmental defects of enamel in primary teeth, asking whether these might be useful as biological markers of the timing and in some cases the nature of insults. Among systemic factors related to development of enamel that might also have implications for neurologic development are certain genetic disorders including tuberous sclerosis, premature birth, neonatal nutritional disturbances (especially hypocalcemia), viral infections (such as rubella and cytomegalovirus during gestation), thyroid disorders, and maternal diabetes. It is concluded that further research is warranted concerning whether developmental defects of dental enamel can be useful markers for the timing of intra-uterine or perinatal events associated with certain neurologic and sensory disorders of children.

Cerebral Palsy↗
PubMed2005

Effects of maternal oral morphine consumption on neural tube development in Wistar rats.

Opiate abuse during pregnancy may result in abnormal nervous system function. In order to evaluate the effects of morphine on the development of the nervous system, the present study focused on the effects of maternal morphine consumption on neural tube development in Wistar rats. Female Wistar rats (250-300 g) were crossed with male rats and coupling time was recorded (embryonic day 0-E0). Experimental groups received 0.1, 0.05, and 0.01 mg/ml of morphine in drinking water daily (14 ml water for each rat). Control group received tap water. On embryonic day 9.5 (E9.5), the animals were anesthetized and the embryos were surgically removed. The embryos were fixed in 10% formalin for 1 week. After this time, weights and lengths (antero-posterior axis--A-P) of the embryos were determined and then tissues were processed, sectioned, and stained in hematoxylin and eosin (H&E). The sections were investigated for neural tube development by light microscope and MOTIC software. The decrease in "A-P" length and embryonic weight for the group that received 0.01 mg/ml morphine was significant. It seems that daily consumption of morphine sulfate could delay neural tube development. In addition, administration of 0.01 mg/ml of morphine led to damage to the regulated neuro-ectoderm layer and its thickness. This study showed that oral morphine consumption leads to neural tube defects, as indicated in the morphometric change and also reduction in weight and length of the embryos. These defects might affect the behavior of the animals.

Administration, Oral↗
PubMed1990

Variation in the response of chick embryos to incision of the roof plate of the neural tube at different developmental stages.

The effects of microsurgical reopening of the neural tube were examined in chick embryos of Stages 12-18. The roof plate of the thoracic neural tube was incised for a length equivalent to 7 somites. The site of incision was studied histologically and by SEM and TEM at intervals up to 48 hours. 48 hours after operation, persistent neural tube defects were more frequent and longer in embryos of more advanced stages at operation. Exposure of embryos to Streptomyces hyaluronidase, which inhibits neurulation in normal embryos, has no effect on the healing of the incised neural tube in the young embryos. Healing of the lesion in younger embryos appeared to occur in two stages: initially, by repair of the surface ectoderm, by a cephalo-caudal zipper-like mechanism, followed by a reconstitution of the roof plate by migration of neurectodermal cells on the deep surface of the ectoderm. Neural tubes of older embryos splay open more widely on incision of the roof plate, apparently making healing mechanically more difficult. This wider splaying may be related to the decline of forces which maintain occlusion of the neural canal in younger embryos.

Animals↗
PubMed1982

Anhidrotic ectodermal dysplasia. Therapeutic attempts.

In 2 patients with anhidrotic ectodermal dysplasia, we were able to show that the hypoplastic eccrine glandular elements may give rise to normal eccrine glands both anatomically and functionally, after repeated local application of acetylcholine. The perspectives of our findings for the therapeutic management of the anhidrotic ectodermal dysplasia are discussed and special attention is paid to the genetic background of the defect as well as the possible mode of action of acetylcholine.

Acetylcholine↗
PubMed2004

Johanson--blizzard syndrome.

Johanson-Blizzard syndrome is an extremely rare ectodermal dysplastic disorder characterized by aplasia or hypoplasia of alae nasi, midline scalp defects, growth retardation, varying degrees of mental retardation, hypothyroidism, exocrine pancreatic insufficiency and congenital deafness. This condition is supposed to be an autosomal recessive disorder. We are reporting a female neonate with the characteristic features and an uncommon less emphasized feature viz. cafe-au-lait spots.

Abnormalities, Multiple↗
PubMed2002

Death receptor signaling giving life to ectodermal organs.

A new tumor necrosis factor (TNF) pathway has been identified that has an important function in the regulation of embryonic development. Three key components of this pathway are previously unknown proteins: the TNF ligand ectodysplasin (also known as EDA), its death domain-containing receptor EDAR, and the death domain adapter molecule EDARADD. This pathway was discovered and delineated through the cloning of genes that cause human hypohidrotic ectodermal dysplasia (HED) syndromes and by analysis of the corresponding mouse mutants (Tabby, downless, and crinkled) showing defects in hair, teeth, and several exocrine glands. EDAR signaling is mediated by the activation of nuclear factor kappa B, but other downstream targets are not known. Ectodysplasin-EDAR signaling mediates cell interactions within the ectoderm and regulates the initiation and morphogenesis of hair and teeth. It is also necessary for the development of fish scales, indicating that this pathway and its function have been conserved during the evolution of ectodermal organs.

Animals↗
PubMed2001

Fibroblast growth factor receptor 2 (Fgfr2) plays an important role in eyelid and skin formation and patterning.

Initiating as protruding ridges above and below the optic vesicle, the eyelids of mice grow across the eye and temporarily fuse in fetal life. Mutations of a number of genes disrupt this developmental process and result in a birth defect, "open-eyelids at birth." Here we show that a critical event for eyelid induction occurs at embryonic day 11.5 (E11.5) when the single cell-layered ectoderm in the presumptive eyelid territory increases proliferation and undergoes morphologic transition to form cube-shaped epithelial cells. Using embryos lacking the Fgfr2 Ig domain III (Fgfr2(DeltaIII/DeltaIII)) generated by tetraploid rescue and chimeric embryo formation approaches, we demonstrate that this event is controlled by Fgfr2 signals as the Fgfr2(DeltaIII/DeltaIII) mutation blocks these changes and results in embryos without eyelids. Fgfr2 and its ligands are differentially expressed in the ectoderm and underlying mesenchyme and function in a reciprocal interacting loop that specifies eyelid development. We also demonstrate that similar defects account for failure of skin formation at early stages. Interestingly, Fgfr2-independent skin formation occurs at E14.5 mutant embryos, resulting in much thinner, yet well-differentiated epidermis. Notably, mutant skin remains thin with decreased hair density after transplantation to wild-type recipients. These data demonstrate an essential role of Fgfr2 in eyelid and skin formation and patterning.

Animals↗
PubMed1976

Ectodermal dysplasia, mental retardation, cleft lip/palate and other anomalies in three sibs.

Three females in a sibship of 10 have a syndrome of mental retardation, ectodermal dysplasia, and cleft lip and/or cleft palate. Inconstant features are congenital skin defects, areas of hyperpigmentation, congenital adhesions between the eyelids, cicatricial atrophy of the scalp, abnormal E.E.G., partial anodontia, genital hypoplasia, syndactyly, and delayed skeletal growth and maturation. The mode of inheritance could be either dominant with incomplete penetrance, or autosomal recessive. The disorder has overlapping features with several previously delineated syndromes but in view of certain novel features its relationship to these is uncertain.

Abnormalities, Multiple↗
PubMed1976

Studies of malformation syndromes of man XXXXIA: anatomical studies in the Hanhart syndrome--a pathogenetic hypothesis.

Two infants with the Hanhart syndrome, i.e. micrognathia, microglossia, terminal deficiency of all limbs and imperforate anus in one, were dissected and studied in detail. The interrelationships of the muscular and skeletal defects suggested that they were the result of incomplete rather than abnormal morphogenesis. We speculate that the oral and limb abnormalities resulted from deficient mesodermal proliferation caused by disturbances in the ectodermal-mesodermal interactions beginning about the 4th week of development. The imperforate anus may also relate to the proposed defect.

Abnormalities, Multiple↗
PubMed1998

Costello syndrome.

Costello syndrome is characterised by postnatal growth deficiency, coarse facies, redundant skin on the neck, palms, soles, and fingers, dark skin, acanthosis nigricans, and papillomata. The natural history evolves in two phases, a severe failure to thrive during the first months contrasting with a normal weight gain in later life. Cardiomyopathy is frequent but other visceral involvement is rare. Mild to moderate mental retardation is usual and most patients exhibit a characteristic sociable and friendly personality. The pathogenesis and molecular basis of the syndrome are unknown and the diagnosis is reliant on clinical expertise. Papillomata represent the most characteristic manifestation but may arise late in life. The peculiar course of the disease, the typical facies, and the ectodermal involvement with loose and hyperpigmented skin are characteristic enough to allow an early diagnosis. Most cases have been sporadic, suggesting de novo dominant mutations.

Abnormalities, Multiple↗