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PubMed1997

Novel regulatory interactions revealed by studies of murine limb pattern in Wnt-7a and En-1 mutants.

Classical embryological experiments have demonstrated that dorsal-ventral patterning of the vertebrate limb is dependent upon ectodermal signals. One such factor is Wnt-7a, a member of the Wnt family of secreted proteins, which is expressed in the dorsal ectoderm. Loss of Wnt-7a results in the appearance of ventral characteristics in the dorsal half of the distal limb. Conversely, En-1, a homeodomain transcription factor, is expressed exclusively in the ventral ectoderm, where it represses Wnt-7a. En-1 mutants have dorsal characteristics in the ventral half of the distal limb. Experiments in the chick suggest that the dorsalizing activity of Wnt-7a in the mesenchyme is mediated through the regulation of the LIM-homeodomain transcription factor Lmx-1. Here we have examined the relationship between Wnt-7a, En-1 and Lmx-1b, a mouse homolog of chick Lmx-1, in patterning the mammalian limb. We find that Wnt-7a is required for Lmx-1b expression in distal limb mesenchyme, and that Lmx-1b activation in the ventral mesenchyme of En-1 mutants requires Wnt-7a. Consistent with Lmx-1b playing a primary role in dorsalization of the limb, we find a direct correlation between regions of the anterior distal limb in which Lmx-lb is misregulated during limb development and the localization of dorsal-ventral patterning defects in Wnt-7a and En-1 mutant adults. Thus, ectopic Wnt-7a expression and Lmx-1b activation underlie the dorsalized En-1 phenotype, although our analysis also reveals a Wnt-7a-independent activity for En-1 in the repression of pigmentation in the ventral epidermis. Finally, we demonstrate that ectopic expression of Wnt-7a in the ventral limb ectoderm of En-1 mutants results in the formation of a second, ventral apical ectodermal ridge (AER) at the junction between Wnt-7a-expressing and nonexpressing ectoderm. Unlike the normal AER, ectopic AER formation is dependent upon Wnt-7a activity, indicating that distinct genetic mechanisms may be involved in primary and secondary AER formation.

Animals↗

PubMed1995

Twenty-four cases of the EEC syndrome: clinical presentation and management.

Twenty-four cases of EEC syndrome were identified as part of a nationwide study. Ectodermal dysplasia, by study definition, was present in all cases and hair and teeth were universally affected. Nail dysplasia was present in 19 subjects (79%) and the skin was affected in 21 (87%). The presence of hypohidrosis was not noted as a predominant feature in the syndrome and its occurrence appeared to depend on the presence of all other features. Distal limb defects from simple syndactyly to tetramelic cleft hand and foot were identified, including preaxial anomalies. Orofacial clefting was identified in 14 cases (58%) and lacrimal duct anomaly in 21 (87%). Significant clinical problems encountered were chiefly cosmetic or ophthalmological, but conductive deafness and genitourinary problems in some cases required surgical intervention. Altered self-image was also noted in some cases. Multidisciplinary management is necessary with the early involvement of the clinical geneticist. Developmentally, the EEC syndrome and related disorders represent disorders of ectodermal/mesodermal interaction. Candidate regions include 7q21.3, the "ectrodactyly" locus; other candidates include developmental genes implicated in the ectodermal/mesodermal interactive process.

Abnormalities, Multiple↗

PubMed1997

Inhibition of chondrogenesis by Wnt gene expression in vivo and in vitro.

The Wnt family of secreted signaling proteins are implicated in regulating morphogenesis and tissue patterning in a wide variety of organ systems. Several Wnt genes are expressed in the developing limbs and head, implying roles in skeletal development. To explore these functions, we have used retroviral gene transfer to express Wnt-1 ectopically in the limb buds and craniofacial region of chick embryos. Infection of wing buds at stage 17 and tissues in the head at stage 10 resulted in skeletal abnormalities whose most consistent defects suggested a localized failure of cartilage formation. To test this hypothesis, we infected micromass cultures of prechondrogenic mesenchyme in vitro and found that expression of Wnt-1 caused a severe block in chondrogenesis. Wnt-7a, a gene endogenously expressed in the limb and facial ectoderm, had a similar inhibitory effect. Further analysis of this phenomenon in vitro showed that Wnt-1 and Wnt-7a had mitogenic effects only in early prechondrogenic mesenchyme, that cell aggregation and formation of the prechondrogenic blastema occurred normally, and that the block to differentiation was at the late-blastema/early-chondroblast stage. These results indicate that Wnt signals can have specific inhibitory effects on cytodifferentiation and suggest that one function of endogenous Wnt proteins in the limbs and face may be to influence skeletal morphology by localized inhibition of chondrogenesis.

Animals↗

PubMed2005

The docking protein FRS2alpha is an essential component of multiple fibroblast growth factor responses during early mouse development.

The docking protein FRS2alpha is a major mediator of fibroblast growth factor (FGF) signaling. However, the physiological role of FRS2alpha in vivo remains unknown. In this report, we show that Frs2alpha-null mouse embryos have a defect in anterior-posterior (A-P) axis formation and are developmentally retarded, resulting in embryonic lethality by embryonic day 8. We demonstrate that FRS2alpha is essential for the maintenance of self-renewing trophoblast stem (TS) cells in response to FGF4 in the extraembryonic ectoderm (ExE) that gives rise to tissues of the placenta. By analyzing chimeric embryos, we found that FRS2alpha also plays a role in cell movement through the primitive streak during gastrulation. In addition, experiments are presented demonstrating that Bmp4 expression in TS cells is controlled by mitogen-activated protein kinase-dependent FGF4 stimulation. Moreover, both the expression of Bmp4 in ExE and activation of Smad1/5 in epiblasts are reduced in Frs2alpha-null embryos. These experiments underscore the critical role of FRS2alpha in mediating multiple processes during embryonic development and reveal a potential new link between FGF and Bmp4 signaling pathways in early embryogenesis.

Animals↗

PubMed2002

The jing Zn-finger transcription factor is a mediator of cellular differentiation in the Drosophila CNS midline and trachea.

We establish that the jing zinc-finger transcription factor plays an essential role in controlling CNS midline and tracheal cell differentiation. jing transcripts and protein accumulate from stage 9 in the CNS midline, trachea and in segmental ectodermal stripes. JING protein localizes to the nuclei of CNS midline and tracheal cells implying a regulatory role during their development. Loss of jing-lacZ expression in homozygous sim mutants and induction of jing-lacZ by ectopic sim expression establish that jing is part of the CNS midline lineage. We have isolated embryonic recessive lethal jing mutations that display genetic interactions in the embryonic CNS midline and trachea, with mutations in the bHLH-PAS genes single-minded and trachealess, and their downstream target genes (slit and breathless). Loss- and gain-of-function jing is associated with defects in CNS axon and tracheal tubule patterning. In jing homozygous mutant embryos, reductions in marker gene expression and inappropriate apoptosis in the CNS midline and trachea establish that jing is essential for the proper differentiation and survival of these lineages. These results establish that jing is a key component of CNS midline and tracheal cell development. Given the similarities between JING and the vertebrate CCAAT-binding protein AEBP2, we propose that jing regulates transcriptional mechanisms in Drosophila embryos and promotes cellular differentiation in ectodermal derivatives.

Animals↗

PubMed1998

Cranial and cardiac neural crest defects in endothelin-A receptor-deficient mice.

Neural crest cells arise in the dorsal aspect of the neural tube and migrate extensively to differentiate into a variety of neural and non-neural tissues. While interactions between neural crest cells and their local environments are required for the proper development of these tissues, little information is available about the molecular nature of the cell-cell interactions in cephalic neural crest development. Here we demonstrate that mice deficient for one type of endothelin receptor, ETA, mimic the human conditions collectively termed CATCH 22 or velocardiofacial syndrome, which include severe craniofacial deformities and defects in the cardiovascular outflow tract. We show that ETA receptor mRNA is expressed by the neural crest-derived ectomesenchymal cells of pharyngeal arches and cardiac outflow tissues, whereas ET-1 ligand mRNA is expressed by arch epithelium, paraxial mesoderm-derived arch core and the arch vessel endothelium. This suggests that paracrine interaction between neural crest-derived cells and both ectoderm and mesoderm is essential in forming the skeleton and connective tissue of the head. Further, we find that pharyngeal arch expression of goosecoid is absent in ETA receptor-deficient mice, placing the transcription factor as one of the possible downstream signals triggered by activation of the ETA receptor. These observations define a novel genetic pathway for inductive communication between cephalic neural crest cells and their environmental counterparts.

Animals↗

PubMed2001

Truncation of the Mll gene in exon 5 by gene targeting leads to early preimplantation lethality of homozygous embryos.

The mixed lineage leukemia gene (MLL) was originally identified through its involvement in reciprocal translocations in leukemias. MLL codes for a large multidomain protein and bears homology to the Drosophila developmental control gene trithorax in two small domains in the amino terminal region, the central zinc finger domain and the carboxy SET domain. Like the Drosophila trx, MLL has also been shown to be a positive regulator of Hox gene expression. We have targeted Mll (the murine homologue of MLL) in exon 5 causing expression of three truncated in-frame Mll transcripts. These transcripts retain all or some of the AT hook motifs and the DMT domain. This mutant allele causes early in vivo preimplantation lethality of homozygous embryos prior to the 2-cell stage. Embryos cultured in vitro progress to the 2-cell stage, but further development is arrested. The heterozygotes exhibit mild skeletal defects as well as defects in some neuroectodermal derivatives.

Animals↗

PubMed2000

The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation.

The homeobox gene Hesx1 is expressed in the anterior visceral endoderm (AVE), anterior axial mesendoderm (AME), and anterior neural ectoderm (ANE) during early mouse embryogenesis. Previous studies have shown that Hesx1 is essential for normal murine forebrain development. Hesx1 homozygous mutants showed variable forebrain truncations ranging from mild to severe lack of forebrain tissue. Here, we have investigated the requirement of Hesx1 in the AVE, AME, and ANE using chimeric and in situ hybridization analyses to understand better the nature of the forebrain defects. Chimeric embryos composed predominantly of Hesx1(+/+) cells developing within Hesx1(-/-) visceral endoderm showed no evident forebrain abnormalities. In contrast, injection of Hesx1(-/-) ES cells into wild-type blastocysts gave rise to chimeras with forebrain defects similar to those observed in the Hesx1(-/-) mutants. RNA in situ hybridization analysis showed that the AVE and AME markers Cerrl, Lim1, and Shh were normally expressed in 6.5- and 7.5-dpc Hesx1(-/-) mutants. Expression of the ANE markers Six3 and Rax/Rx was also unperturbed in the Hesx1(-/-) mutants from late gastrula to late headfold stages. However, transcripts for both genes were markedly reduced by the early somite stage, about 24 h after Hesx1 is first expressed in the ANE. Therefore, Hesx1 seems to be required autonomously in the ANE for normal forebrain formation.

Animals↗

PubMed1994

[Anhidrotic ectodermal dysplasia. Disorder of the differentiation of hair follicles and sweat glands leads to abnormal keratinization].

We report on an 11-year-old female patient with anhidrotic ectodermal dysplasia (AED) showing the following characteristics: (1) reduced number of hair follicles and incomplete formation of sweat glands; (2) disturbed hair growth with shortening of anagen and anhidrosis; (3) disturbed cytokeratin expression pattern of CK 13, 14, 19 (follicular epithelium) and of CK 18 (eccrine sweat glands); (4) reduction of cystine and increase in sulphonic cysteine acid. Thus, we demonstrated pathological differentiation on the immunomorphological and on the biochemical level, leading to disturbed keratinization that could be visualized by transmission and scanning electron microscopical studies of the hair shafts. According to these findings AED is a developmental defect that involves not only incomplete formation of hair follicles and sweat glands but also a disordered differentiation and follicular keratinization with disturbed cytokeratin pattern and pathological amino acid composition of the terminal hairs produced.

Antibodies, Monoclonal↗

PubMed2002

The mouse PcG gene eed is required for Hox gene repression and extraembryonic development.

The Polycomb group (PcG) of genes was first identified in Drosophila as maintenance factors for long-term transcriptional repression of homeotic genes. In mice, the PcG protein Eed (Embryonic ectoderm development) is present in a distinct complex that interacts with histone deacetylase (HDAC) and the PcG member Ezh2 (Enhancer of zeste homolog 2), but not in the larger Polycomb repressive complex 1 (PRC1) formed by several other PcG proteins. eednull mutants manifest a distinct early gastrulation defect that occurs prior to homeotic gene expression. To determine whether Eed is also required for regulating homeotic genes, a later acting eedhypomorph mutation was analyzed. The anterior expression boundaries of several Hox genes were shifted rostrally by one segment, indicating that Eed is required for stable repression of homeotic genes. Furthermore, although the eednull/hypomorph compound heterozygotes die during mid-gestation stage, they did not show a more severe derepression of Hox genes than the eedhypomorph/hypomorph homozygotes. A detailed analysis of the mid-gestation lethality associated with the eednull/hypomorph compound heterozygotes revealed a novel function for eed in the development of secondary trophoblast giant cells during murine placenta formation. Tetraploid rescue experiments demonstrated that the defect is cell autonomous in the extraembryonic lineage. Mash2, a paternally imprinted gene important for trophoblast development, was ectopically expressed in the eed mutants. However, genetic crosses with a Mash2 null allele suggested that Eed was not required to maintain Mash2 imprinting, but could be required in a lineage specific fashion to suppress Mash2 expression.

Animals↗

PubMed1999

Dynamic features of adherens junctions during Drosophila embryonic epithelial morphogenesis revealed by a Dalpha-catenin-GFP fusion protein.

Cell-cell adherens junctions (AJs), comprised of the cadherin-catenin adhesion system, contribute to cell shape changes and cell movements in epithelial morphogenesis. However, little is known about the dynamic features of AJs in cells of the developing embryo. In this study, we constructed Dalpha-catenin fused with a green fluorescent protein (Dalpha-catenin-GFP), and found that it targeted apically located AJ-based contacts but not other lateral contacts in epithelial cells of living Drosophila embryos. Using time-lapse fluorescence microscopy, we examined the dynamic performance of AJs containing Dalpha-catenin-GFP in epithelial morphogenetic movements. In the ventral ectoderm of stage 11 embryos, concentration and deconcentration of Dalpha-catenin-GFP occurred concomitantly with changes in length of AJ contacts. In the lateral ectoderm of embryos at the same stage, dynamic behaviour of AJs was concerted with division and delamination of sensory organ precursor (SOP) cells. Moreover, changes in patterns of AJ networks during tracheal extension could be followed. Finally, we utilized Dalpha-catenin-GFP to precisely observe the defects in tracheal fusion in shotgun mutants. Thus, the Dalpha-catenin-GFP fusion protein is a helpful tool to simultaneously observe morphogenetic movements and AJ dynamics at high spatio-temporal resolution.

Animals↗

PubMed1999

Characterization of the Tribolium Deformed ortholog and its ability to directly regulate Deformed target genes in the rescue of a Drosophila Deformed null mutant.

We have analyzed the Tribolium castaneum ortholog of the Drosophila homeotic gene Deformed (Dfd) and determined its expression pattern during embryogenesis in this beetle. Tc Deformed (Tc Dfd) is expressed in the blastoderm and the condensing germ rudiment in a region that gives rise to gnathal segments. During germ band extension Tc Dfd is expressed in the mandibular and maxillary segments, their appendages, and the dorsal ridge. Comparison of insect Dfd protein sequences reveals several highly conserved regions. To determine whether common molecular features reflect conserved regulatory functions we used the Gal4 system to express the Tribolium protein in Drosophila embryos. When Tc Dfd is expressed throughout embryonic ectoderm under the control of P69B, the beetle protein autoregulates the endogenous Dfd gene. In addition, the Drosophila proboscipedia gene (a normal target of Dfd) is ectopically activated in the antennal and thoracic segments. We also compared the ability of the beetle and fly proteins to rescue defects in Dfd- mutants by expressing each throughout the embryonic during embryogenesis. Both proteins rescued Dfd- defects to the same extent in that they each restore the development of mouth hooks and cirri, as well as cause gain-of-function abnormalities of posterior mouth parts. As before, pb was ectopically activated in the antennal segment. This is the first demonstration of the ability of a heterologous homeotic selector protein to directly regulate a target gene independent of an endogenous Drosophila autoregulatory loop.

Amino Acid Sequence↗

PubMed1993

A severe case of Beare-Stevenson syndrome and associated congenital deformities.

A severe case of congenital anomalies is described, with several characteristics of Beare-Stevenson syndrome, such as cutis gyrata, acanthosis nigricans, craniofacial anomalies, ear defects, enlarged umbilical stump and anogenital anomalies. He does not have craniosynostosis or clover leaf skull, which has also been described in this syndrome. This patient also shows hands and feet anomalies, absence of skin adnexa in several locations and dental anomalies, which could suggest an associated ectodermal dysplasia.

Abnormalities, Multiple↗

PubMed2003

Segment polarity and DV patterning gene expression reveals segmental organization of the Drosophila brain.

The insect brain is traditionally subdivided into the trito-, deuto- and protocerebrum. However, both the neuromeric status and the course of the borders between these regions are unclear. The Drosophila embryonic brain develops from the procephalic neurogenic region of the ectoderm, which gives rise to a bilaterally symmetrical array of about 100 neuronal precursor cells, called neuroblasts. Based on a detailed description of the spatiotemporal development of the entire population of embryonic brain neuroblasts, we carried out a comprehensive analysis of the expression of segment polarity genes (engrailed, wingless, hedgehog, gooseberry distal, mirror) and DV patterning genes (muscle segment homeobox, intermediate neuroblast defective, ventral nervous system defective) in the procephalic neuroectoderm and the neuroblast layer (until stage 11, when all neuroblasts are formed). The data provide new insight into the segmental organization of the procephalic neuroectodem and evolving brain. The expression patterns allow the drawing of clear demarcations between trito-, deuto- and protocerebrum at the level of identified neuroblasts. Furthermore, we provide evidence indicating that the protocerebrum (most anterior part of the brain) is composed of two neuromeres that belong to the ocular and labral segment, respectively. These protocerebral neuromeres are much more derived compared with the trito- and deutocerebrum. The labral neuromere is confined to the posterior segmental compartment. Finally, similarities in the expression of DV patterning genes between the Drosophila and vertebrate brains are discussed.

Animals↗

PubMed1993

Acalvaria: a unique congenital anomaly.

Acalvaria is a rare malformation usually regarded as a postneurulation defect. It consists of absence of the calvarial bones, dura mater and associated muscles in the presence of a normal skull base and normal facial bones. The condition is frequently confused by prenatal ultrasonography with anencephaly or an encephalocele. Whereas the cerebral hemispheres are absent in anencephaly, the cranial contents in acalvaria are generally complete, though some neuropathological abnormality is often present. The presumed pathogenesis of acalvaria is faulty migration of the membranous neurocranium with normal placement of the embryonic ectoderm, resulting in absence of the calvaria but an intact layer of skin over the brain parenchyma. We describe 2 cases of acalvaria, one misdiagnosed ultrasonographically as an occipital encephalocele prenatally. The brain in one fetus demonstrated semilobar holoprosencephaly and micropolygyria, but in the other, was structurally and histologically normal with the exception of hydrocephalus.

Abortion, Therapeutic↗

PubMed2006

Loss of nidogen-1 and -2 results in syndactyly and changes in limb development.

Nidogens are two ubiquitous basement membrane proteins produced mainly by mesenchymal cells. Nidogen-mediated interactions, in particular with laminin, collagen IV, and perlecan have been considered important in the formation and maintenance of the basement membrane. However, whereas mice lacking both nidogen isoforms or carrying mutations in the high affinity nidogen-binding site upon the laminin gamma1 chain have specific basement membrane defects in certain organs, particularly in the lung, characterization of these mice has also shown that basement membrane formation per se does not need nidogens or the laminin-nidogen interaction. Limb development requires the complex interplay of numerous growth factors whose expression is dependent upon the apical ectodermal ridge. Here, we show that lack of nidogen-1 and -2 results in a specific and time-limited failure in the ectodermal basement membrane of the limb bud. The absence of this basement membrane leads to aberrant apical ectodermal ridge formation. It also causes altered distribution of growth factors, such as fibroblast growth factors and leads to a fully penetrant soft tissue syndactyly caused by the dysregulation of interdigital apoptosis. Further, in certain animals more severe changes in bone formation occur, providing evidence for the interplay between growth factors and the extracellular matrix.

Animals↗

PubMed2004

Use of a water-vapour permeable polyurethane film (omiderm) in the non-surgical treatment of aplasia cutis congenita.

Aplasia cutis congenita is characterised by congenital absence of all layers of skin, and most commonly affects the scalp. It is often associated with absence of the bone and dura underlining the defective scalp. In this report, we present the result of use of a water-vapour permeable polyurethane film (Omiderm) together with absorbant fine mesh gauze impregnated with 3% bismuth tribromophenate (Xeroform) in the treatment of a cranial defect in a newborn baby of low birth weight, who could not be operated on because of associated medical problems.

Bandages↗

PubMed1998

[Dorso-ventral patterning of the vertebrate limb and dermatoglyphs with special reference to the pad pattern of mice].

The proximo-distal (P-D), antero-posterior (A-P) and dorso-ventral (D-V) axes are important for normal limb development in vertebrates. It has been reported that D-V axis is decided by Wnt-7a, Lmx-1 and Engrailed-1 (En-1) which are expressed in the limb bud along D-V axis. These factors are thought to be required for formation of the apical ectodermal ridge (AER) which is necessary for outgrowth of the limb. The results from spontaneous mutant mice meromelia (mem), which exhibits double-dorsality of the distal limb, suggested that other factors, not only En-1 and Wnt-7a are required for decision of AER, and mem was probed to be novel gene regulating En-1 and Wnt-7a directly or indirectly. The dorsalized ventral structures in meromelia were found by observation of the pad pattern. Pad pattern is always constant in normal mice, and each pad indicates particular part of the limb. So pad pattern is useful to detect and describe anomalies even in the limbs without skeletal defects. The process of pad development is associated with the limb patterning, and abnormal pad pattern may indicate pathogenesis of abnormal limb development. The mouse pad pattern is usable as the model for human dermatoglyphs, and it is also important to investigate mechanisms of human diseases.

Animals↗