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PubMed2005

Aplasia cutis congenita, skull defect, brain heterotopia, and intestinal lymphangiectasia.

We describe a female infant with a previously unreported combination of manifestations characterized by aplasia cutis, skull defect, brain heterotopia, mild congenital lymphedema, and intestinal lymphangiectasia. The association of intestinal lymphangiectasia and aplasia cutis, and the association of intestinal lymphangiectasia with brain heterotopia in the lymphedema-lymphangiectasia-mental retardation syndrome have been described in single reports. In one family, the association of cortical dysplasia and congenital lymphedema have been related to mutations in the RELN gene.

Abnormalities, Multiple↗
PubMed2003

Alk8 is required for neural crest cell formation and development of pharyngeal arch cartilages.

The type I TGFbeta family member receptor alk8 acts in bone morphogenetic protein (BMP) signaling pathways to establish dorsoventral patterning in the early zebrafish embryo. Here, we present evidence that alk8 is required for neural crest cell (NCC) formation and that alk8 signaling gradients direct the proper patterning of premigratory NCCs. We extend our previous functional studies of alk8 to demonstrate that ectopic expression of constitutively active and dominant negative Alk8, consistently results in more medially or laterally positioned premigratory NCCs, respectively. We also demonstrate that patterning defects in premigratory NCCs, induced by alk8 misexpression, correlate with subsequent defects in NCC-derived pharyngeal arch cartilages. Furthermore, an anteroposterior effect is revealed, where overexpression of Alk8 more severely affects anterior arch cartilages and decreased Alk8 activity more severely affects posterior arch cartilage formation. Ectopic expression studies of alk8 are supported by analyses of zygotic and maternal-zygotic laf/alk8 mutants and of several BMP pathway mutants. Pharyngeal mesodermal and endodermal defects in laf/alk8 mutants suggest additional roles for alk8 in patterning of these tissues. Our results provide insight into alk8-mediated BMP signaling gradients and the establishment of premigratory NCC mediolateral positioning, and extend the model for BMP patterning of the neural crest to include that of NCC-derived pharyngeal arch cartilages.

Activin Receptors, Type I↗
PubMed1999

The wide spectrum of clinical expression in Adams-Oliver syndrome: a report of two cases.

Two children are described with the combination of aplasia cutis congenita (ACC) and transverse limb defects known as Adams-Oliver syndrome. Whereas in the first child the typical features of ACC, syndactyly and transverse nail dystrophy were only mildly expressed and associated defects of the central nervous system and cardiac malformations were absent, the second child suffered from a very severe expression of the syndrome, with a combination of ACC, syndactyly, cutis marmorata telangiectatica congenita and multiple cardiac and central nervous system malformations which resulted in fatal central respiratory insufficiency.

Abnormalities, Multiple↗
PubMed2001

Inductive signals from the somatopleure mediated by bone morphogenetic proteins are essential for the formation of the sternal component of avian ribs.

The posterior five pairs of avian ribs are composed of vertebral and sternal components, both derived from the somitic mesoderm. For the patterning of the rib cartilage, inductive signals from neighboring tissues on the somitic mesoderm have been suggested to play critical roles. The notochord and surface ectoderm overlying the somitic mesoderm are essentially required for the development of proximal and distal regions of the ribs, respectively. Involvement of the somatopleure in rib development has already been suggested but is less understood than those of the notochord and surface ectoderm. In this study, we reinvestigated the role of the somatopleure during rib development. We first identified the chicken homologue of the mouse Mesenchymal forkhead-1 (cMfh-1) gene based on sequence similarities. cMfh-1 was observed to be expressed in the nonaxial mesoderm, including the somitic mesoderm, and, subsequently, in cartilage forming the ribs, vertebrae, and appendicular skeletal system. In the interlimb region, corresponding to somites 21-25 (or 26), cMfh-1-positive somitic mesoderm was seen penetrating the somatopleure of E4 embryos, and cMfh-1 was used as a molecular marker demarcating prospective rib cartilage. A series of experiments affecting the penetration of the somitic mesoderm into the somatopleure was performed in the present study, resulting in defects in sternal rib formation. The inductive signals emanating from the somatopleure mediated by BMP family proteins were observed to be essentially involved in the ingrowth of the somitic mesoderm. BMP4 alone, however, could not completely replace inductive signals from the somatopleure, suggesting the involvement of additional signals for rib formation.

Amino Acid Sequence↗
PubMed1999

Regional specification during embryogenesis in the inarticulate brachiopod Discinisca.

The process of embryogenesis is described for the inarticulate brachiopod Discinisca strigata of the family Discinidae. A fate map has been constructed for the early embryo. The animal half of the egg forms the dorsal ectoderm of the apical and mantle lobes. The vegetal half forms mesoderm and endoderm and is the site of gastrulation; it also forms the ectoderm of the ventral regions of the apical and mantle lobes of the larva. The plane of the first cleavage goes through the animal-vegetal axis of the egg along the future plane of bilateral symmetry of the larva. The timing of regional specification in these embryos was examined by isolating animal, vegetal, or lateral regions at different times from the 2-cell stage through gastrulation. Animal halves isolated at the 8-cell and blastula stages formed an epithelial vesicle and did not gastrulate. When these halves were isolated from blastulae they formed the cell types typical of apical and mantle lobes. Vegetal halves isolated at all stages gastrulated and formed a more or less normal larva; the only defect these larvae had was the lack of an apical tuft, which normally forms from cells at the animal pole of the embryo. When lateral isolates were created at all developmental stages, these halves gastrulated. Cuts which separated presumptive anterior and posterior regions generated isolates at the 4-cell and blastula stages that formed essentially normal larvae; however, at the midgastrula stage these halves formed primarily anterior or posterior structures indicating that regional specification had taken place along the anterior-posterior axis. The plane of the first cleavage, which predicts the plane of bilateral symmetry, can be shifted by either changing the cleavage pattern that generates the bilateral 16-cell blastomere configuration or by isolating embryo halves prior to, or during, the 16-cell stage. These results indicate that while the plane of the first cleavage predicts the axis of bilateral symmetry, the axis is not established until the fourth cleavage. The development of Discinisca is compared to development in the inarticulate brachiopod Glottidia of the family Lingulidae and to Phoronis in the phylum Phoronida.

Animals↗
PubMed1995

Johanson-Blizzard syndrome facial anomaly and its correction using a microsurgical bone graft and tripartite osteotomy.

The facial anomaly of Johanson-Blizzard syndrome and its correction are described. The facial anomaly was characterized by cleft-like bony defects located in the inferomedial portion of the orbit apart from the hypoplastic maxilla and the absence of nasal alae. Correction of the facial skeleton was performed using a free vascularized iliac bone graft and tripartite osteotomy to correct the shape of the orbit and elongate the severely hypoplastic maxilla. Those procedures were effective to a certain degree in correcting the facial anomaly of Johanson-Blizzard syndrome.

Bone Lengthening↗
PubMed2005

The genetic basis of pachyonychia congenita.

In 1994, the molecular basis of pachyonychia congenita (PC) was elucidated. Four keratin genes are associated with the major subtypes of PC: K6a or K16 defects cause PC-1; and mutations in K6b or K17 cause PC-2. Mutations in keratins, the epithelial-specific intermediate filament proteins, result in aberrant cytoskeletal networks which present clinically as a variety of epithelial fragility phenotypes. To date, mutations in 20 keratin genes are associated with human disorders. Here, we review the genetic basis of PC and report 30 new PC mutations. Of these, 25 mutations were found in PC-1 families and five mutations were identified in PC-2 kindreds. All mutations identified were heterozygous amino acid substitutions or small in-frame deletion mutations with the exception of an unusual mutation in a sporadic case of PC-1. The latter carried a 117 bp duplication resulting in a 39 amino acid insertion in the 2B domain of K6a. Also of note was mutation L388P in K17, which is the first genetic defect identified in the helix termination motif of this protein. Understanding the genetic basis of these disorders allows better counseling for patients and paves the way for therapy development.

Base Sequence↗
PubMed1995

The limb deformity mutation disrupts the SHH/FGF-4 feedback loop and regulation of 5' HoxD genes during limb pattern formation.

Mutations in the murine limb deformity (ld) gene disrupt differentiation of the Apical Ectodermal Ridge (AER) and patterning of distal limb structures. However, initial outgrowth of the limb bud is not affected, suggesting that early and late functions of the AER are uncoupled. Similarly, activation of the 5' members of the HoxD gene cluster (Hoxd-11 to Hoxd-13) is not affected in ld mutant posterior limb bud mesenchyme, but the subsequent anteriorization of 5' HoxD domains is delayed by about 12 hours and is associated with reduced levels of polarising activity. These results indicate that the ld gene products act upstream of 5' HoxD genes during patterning of the autopod. Expression of the signalling molecule Sonic hedgehog (Shh) in the posterior limb bud mesenchyme is initiated normally, but ceases prematurely indicating a defect in maintenance of Shh by the ld mutant AER. Furthermore, no Fgf-4 transcripts are detected in the ld mutant AER, whereas Fgf-8 transcripts remain expressed. However, Shh expression can be rescued by heterospecific grafting of ld mutant posterior mesenchyme under a wild-type chicken AER. These studies show that the AER defect in ld homozygous limb buds causes disruption of the FGF-4/SHH feedback loop and support the proposed essential role for FGF-4 in maintaining Shh expression during limb pattern formation.

Animals↗
PubMed2002

Hindbrain and cranial nerve dysmorphogenesis result from acute maternal ethanol administration.

Acute exposure of mouse embryos to ethanol during stages of hindbrain segmentation results in excessive cell death in specific cell populations. This study details the ethanol-induced cell loss and defines the subsequent effects of this early insult on rhombomere and cranial nerve development. Ethanol at a teratogenic dosage (2.9 g/kg) or a comparable volume of vehicle was administered in each of two intraperitoneal injections to pregnant C57BL/6J mice on gestational day (GD) 8, 8 h, and GD 8, 12 h (defined hereafter as GD 8.5). Ethanol-exposed GD 9 embryos, visualized in three dimensions using laser scanning confocal microscopy of LysoTracker Red fluorescence or Nile blue sulphate vital staining, displayed excessive apoptosis in the rostral hindbrain, specifically within rhombomeres 1-3, as well as in cranial neural crest cells and ectodermal placodes. Comparably treated embryos examined on GD 10.5-11 illustrated a disproportionate reduction in the length of the rostral hindbrain. Examination of plastic histological sections of GD 9 embryos and via scanning electron microscopy on GD 10 revealed deficiencies in the hindbrain, with a phenotype including abnormal rhombomere segmentation and an extremely small fourth ventricular roofplate. Whole-mount antineurofilament immunohistochemistry on GD 10.5 and GD 11 illustrated a variety of cranial nerve abnormalities ranging from fused or absent ganglia to ectopic or disorganized fibers. In addition, a delay in the development of the glossopharyngeal (IX) nerve/ganglia complex was observed. These hindbrain and cranial nerve abnormalities are discussed in the context of the genesis of human alcohol-related birth defects and neurodevelopmental disorder.

Alcohol-Induced Disorders, Nervous System↗
PubMed2002

Expression of the bHLH transcription factor Tcf12 (ME1) gene is linked to the expansion of precursor cell populations during neurogenesis.

In this study, we focused on the potential function of the murine gene Tcf12 (also known as ME1 or HEB) encoding the bHLH E-protein ME1 during brain development. An exencephaly phenotype of low penetrance has consistently been observed in both Tcf12 null mice and Tcf12(dm) homozygous mice. Thus, to address the possible underlying mechanism of the Tcf12 gene during the early steps of brain development, we performed a detailed analysis of its spatio-temporal expression pattern at distinct steps of gastrulation and neurogenesis. We found that Tcf12 transcripts are detected in the embryonic ectoderm prior to neural induction during gastrulation. During neurulation, Tcf12 transcripts are evident at high levels in the proliferating neuroepithelium of the neural folds and the cephalic mesenchyme. Thus, Tcf12 gene expression coincides with the massive proliferation occurring in the forming neuroepithelium and cephalic mesenchyme during neural tube formation, which is consistent with the exencephaly phenotype of Tcf12 null mice. In the developing cortex and spinal cord, Tcf12 expression is restricted to the proliferative ventricular zones, indicating that Tcf12 expression is down regulated when these neuronal cells undergo their final differentiation. Interestingly, we found that the postnatal Tcf12 expression parallels the ongoing adult neurogenesis in the mitotically active subventricular zone. Thus, the timing and location of Tcf12 expression combined with this severe neurulation defect support our hypothesis that the Tcf12 gene may be involved in the control of proliferating neural stem cells and progenitor cells and that it may be critical to sustain their undifferentiated state during embryonic and adult neurogenesis.

Animals↗
PubMed1974

[Cellular heredity, its alteration and organ restoration].

Patterns of cell heredity in vertebrates and possibility of its alteration, i. e. artificial tissue metaplasia, are considered. These problems are compared with the well studied phenomenon of metaplasia in eyes of the newt in which the removal of some parts of the eye leads to natural metaplasia, an initial step for restoration of eye parts. A brief analysis of sequence of inductive processes in development shows that by the end of the period of induction and the onset of terminal differentiation the maximum concentration of specific inducing agents in induced rudiments can be expected. This suggestion was confirmed by the experiments of specific assimilatory induction in gastrula ectoderm and artificial conversion of pigmented epithelium in retina and lens tissues. On the basis of the data reported and in comparison with the theories of intragenomic regulation, a new hypothesis of cell heredity is put forward. The basic idea of this hypothesis is that the regulatory genes can switch on the genes responsible for the synthesis of terminal proteins via inducing proteins; the latter can simultaneously programm the function of regulatory genes, initiating their own synthesis. Due to such a feedback mechanism forming during development, stable cell types arise. Their inheritance can be altered by the introduction of new inducing agents in parallel with the elimination of conditions stabilizing cell differentiation. Possible ways for application of artificial metaplasia for restoration of eye defects in medical practice are considered.

Animals↗
PubMed1996

The role of fibroblast growth factors in early Xenopus development.

In recent years we and others have been attempting to identify the molecular nature of the inducing signals in early Xenopus development. We have found that most members of the fibroblast growth factor (FGF) family are biologically active as mesoderm-inducing factors when applied to ectoderm from blastulae. In addition to this, they will support continued expression of the pan-mesodermal transcription factor Xbra in the mesoderm of gastrula stage embryos. We have studied the expression pattern of four types of FGF in early embryos. Two types (FGF-2 and FGF-9) are expressed maternally and are thus present at the time of natural mesoderm induction. The expression of two other types (FGF-3 and FGF-4) is activated in the newly formed mesoderm of the gastrula. If the activity of the FGF family is inhibited by overexpression of a dominant-negative FGF receptor, there is a reduction in mesoderm formation, there are abnormalities arising from an inhibition of normal gastrulation movements and there is a defect in formation of the posterior parts. We believe that the mesoderm formation and cell movement effects are attributable to loss of Xbra expression, and the posterior defects to lack of posterior HOX gene activity. Overexpression of eFGF gives rise to a posteriorized phenotype, in which posterior HOX genes are expressed in a more anterior position. We conclude that the FGF system has multiple functions in early development, including mesoderm formation, gastrulation movements and anteroposterior patterning.

Animals↗
PubMed2002

Aire deficient mice develop multiple features of APECED phenotype and show altered immune response.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a monogenic autosomal recessive disease caused by mutations in the AIRE gene. Here we have produced knock-out mice for the Aire gene. The Aire-/- mice develop normally; however, autoimmune features of APECED in Aire-/- mice are evident, including multiorgan lymphocytic infiltration, circulating autoantibodies and infertility. The distribution of B and T cells and thymic maturation as well as activation of T cells appear normal, while the TCR-Vbeta repertoire is altered in peripheral T cells of Aire-/- mice. When mice are challenged with immunization, the peripheral T cells of Aire-/- mice have a 3-5-fold increased proliferation. These findings suggest that the Aire gene is not necessary for normal T cell education and development, while a defect in immune response detected in challenged Aire-/- mice underlines the crucial role of AIRE/Aire in maintaining homeostatic regulation in the immune system.

Animals↗
PubMed1995

Normal expression and the effects of ectopic expression of the Drosophila muscle segment homeobox (msh) gene suggest a role in differentiation and patterning of embryonic muscles.

Myogenesis is a several step process that requires genes involved in specifying mesoderm lineage and genes involved in determining muscle identity, differentiation, and patterning. We report here on the isolation, characterization, and expression pattern of a cDNA clone encoded by the previously uncharacterized Drosophila muscle segment homeobox (msh) gene and its possible role in myogenesis. The amino acid sequence of the msh homeobox domain is highly homologous to the homeodomains of the Drosophila S59 and empty spiracles genes and the Hox 7 and Hox 8 family of vertebrate homeobox genes. In addition, the 5' end of msh has 52% sequence identity to the 5' end of the empty spiracles gene and encodes several stretches of amino acids rich in serine, alanine, proline, glutamine, and acidic amino acids, indicating potential domains of regulatory activity. The expression of msh is initially detected at about stage 6 in the dorsal lateral ectoderm of the embryo and later in the developing central (CNS) and peripheral nervous systems. During germ band retraction (stage 12), msh continues to be expressed in cells of the nervous system as well as cells of the somatic mesoderm corresponding mostly to the developing dorsal and lateral somatic body wall muscles. These mesodermal cells, which continue to express msh in daughterless mutant embryos, undergo an increase in cell number in neurogenic mutants. By late stage 14 of embryonic development, msh expression is greatly reduced or absent in most or all mesoderm and muscle but continues in CNS until hatching. Ectopic expression of msh in the mesoderm results in altered expression of the S59 and nau/Dmyd genes leading to a loss of some muscles and defects in the patterning of others, suggesting that the muscle defects are at the level of recruitment and/or patterning of muscle precursor cells. Thus the similarity of Drosophila msh expression to that of the homologous vertebrate Hox 7 and Hox 8 genes together with the effects of ectopic expression of msh in the mesoderm suggest a role for the msh-like family of genes in mesodermal and muscle differentiation and patterning.

Amino Acid Sequence↗
PubMed1999

Hindlimb patterning and mandible development require the Ptx1 gene.

The restricted expression of the Ptx1 (Pitx1) gene in the posterior half of the lateral plate mesoderm has suggested that it may play a role in specification of posterior structures, in particular, specification of hindlimb identity. Ptx1 is also expressed in the most anterior ectoderm, the stomodeum, and in the first branchial arch. Ptx1 expression overlaps with that of Ptx2 in stomodeum and in posterior left lateral plate mesoderm. We now show that targeted inactivation of the mouse Ptx1 gene severely impairs hindlimb development: the ilium and knee cartilage are absent and the long bones are underdeveloped. Greater reduction of the right femur size in Ptx1 null mice suggests partial compensation by Ptx2 on the left side. The similarly sized tibia and fibula of mutant hindlimbs may be taken to resemble forelimb bones: however, the mutant limb buds appear to have retained their molecular identity as assessed by forelimb expression of Tbx5 and by hindlimb expression of Tbx4, even though Tbx4 expression is decreased in Ptx1 null mice. The hindlimb defects appear to be, at least partly, due to abnormal chondrogenesis. Since the most affected structures derive from the dorsal side of hindlimb buds, the data suggest that Ptx1 is responsible for patterning of these dorsal structures and that as such it may control development of hindlimb-specific features. Ptx1 inactivation also leads to loss of bones derived from the proximal part of the mandibular mesenchyme. The dual role of Ptx1 revealed by the gene knockout may reflect features of the mammalian jaw and hindlimbs that were acquired at a similar time during tetrapod evolution.

Animals↗
PubMed2002

Spiel-ohne-grenzen/pou2 mediates regional competence to respond to Fgf8 during zebrafish early neural development.

Neural patterning of the vertebrate brain starts within the ectoderm during gastrulation and requires the activity of organizer cell populations in the neurectoderm. One such organizer is located at the prospective midbrain-hindbrain boundary (MHB) and controls development of the midbrain and the anterior hindbrain via the secreted signaling molecule Fgf8. However, little is known about how the ability of neural precursors to respond to Fgf8 is regulated. We have studied the function of the zebrafish spiel-ohne-grenzen (spg) gene in early neural development. Genetic mapping and molecular characterization presented in the accompanying paper revealed that spg mutations disrupt the pou2 gene, which encodes a POU domain transcription factor that is specifically expressed in the MHB primordium, and is orthologous to mammalian Oct3/Oct4. We show that embryos homozygous for spg/pou2 have severe defects in development of the midbrain and hindbrain primordium. Key molecules that function in the formation of the MHB, such as pax2.1, spry4, wnt1, her5, eng2 and eng3, and in hindbrain development, such as krox20, gbx2, fkd3 and pou2, are all abnormal in spg mutant embryos. By contrast, regional definition of the future MHB in the neuroectoderm by complementary expression of otx2 and gbx1, before the establishment of the complex regulatory cascade at the MHB, is normal in spg embryos. Moreover, the Fgf8 and Wnt1 signaling pathways are activated normally at the MHB but become dependent on spg towards the end of gastrulation. Therefore, spg plays a crucial role both in establishing and in maintaining development of the MHB primordium. Transplantation chimeras show that normal spg function is required within the neuroectoderm but not the endomesoderm. Importantly, gain-of-function experiments by mRNA injection of fgf8 and pou2 or Fgf8 bead implantations, as well as analysis of spg-ace double mutants show that spg embryos are insensitive to Fgf8, although Fgf receptor expression and activity of the downstream MAP kinase signaling pathway appear intact. We suggest that spg/pou2 is a transcription factor that mediates regional competence to respond to Fgf8 signaling.

Animals↗
PubMed2004

Loss of PGC-specific expression of the orphan nuclear receptor ERR-beta results in reduction of germ cell number in mouse embryos.

Estrogen related receptor beta (ERR-beta) is an orphan nuclear receptor specifically expressed in a subset of extra-embryonic ectoderm of post-implantation embryos. ERR-beta is essential for placental development since the ERR-beta null mutants die at 10.5dpc due to the placenta abnormality. Here, we show that the ERR-beta is specifically expressed in primordial germ cells (PGC), obviously another important cell type for reproduction. Expression of the ERR-beta mRNA in embryonic germ cells started at E11.5 as soon as PGC reached genital ridges, and persisted until E15-E16 in both sexes. Immunostaining with anti-ERR-beta antibody revealed that the ERR-beta protein is exclusively expressed in germ cells in both male and female gonads from E11.5 to E16. 5. To study function of the ERR-beta in PGC, we complemented placental defects of the ERR-beta null mutants with wild-type tetraploid embryos, and analyzed germ cell development in the rescued embryos. It was found that development of gonad and PGC was not apparently affected, but number of germ cells was significantly reduced in male and female gonads, suggesting that the ERR-beta appears to be involved in proliferation of gonadal germ cells. The rescued embryos could develop to term and grow up to adulthood. The rescued ERR-beta null male were found to be fertile, but both male and female null mutants exhibited behavioural abnormalities, implying that the ERR-beta plays important roles in wider biological processes than previously thought.

Animals↗
PubMed2004

IkappaB kinase-alpha acts in the epidermis to control skeletal and craniofacial morphogenesis.

IkappaB kinase-alpha (IKK-alpha) exhibits protein-kinase-dependent and -independent functions. Its kinase activity is required for lymphoid organogenesis and mammary gland development, whereas a kinase-independent activity is required for epidermal keratinocyte differentiation. In addition to failed epidermal differentiation, IKK-alpha-deficient mice exhibit abnormal skeletal and craniofacial morphogenesis. As similar defects are not exhibited by mice that experience systemic inhibition of NF-kappaB, we postulated that the morphogenetic defects in IKK-alpha-deficient mice are not caused by reduced NF-kappaB activity but instead are due to failed epidermal differentiation that disrupts proper epidermal-mesodermal interactions. We tested this hypothesis by introducing an epidermal-specific Ikka (also known as Chuk) transgene into IKK-alpha-deficient mice. Mice lacking IKK-alpha in all cell types including bone and cartilage, but not in basal epidermal keratinocytes, exhibit normal epidermal differentiation and skeletal morphology. Thus, epidermal differentiation is required for proper morphogenesis of mesodermally derived skeletal elements. One way by which IKK-alpha controls skeletal and craniofacial morphogenesis is by repressing expression of fibroblast growth factor (FGF) family members, such as FGF8, whose expression is specifically elevated in the limb bud ectoderm of IKK-alpha-deficient mice.

Animals↗