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Apical Ectodermal Ridge (apical + ectodermal_ridge)
Selected AbstractsBusulfan-induced central polydactyly, syndactyly and cleft hand or foot: A common mechanism of disruption leads to divergent phenotypesDEVELOPMENT GROWTH & DIFFERENTIATION, Issue 6 2007Takuji Naruse The prevalence of clinical phenotypes that exhibit combinations of central polydactyly, syndactyly, or cleft hand or foot is higher than would be expected for random independent mutations. We have previously demonstrated that maternal ingestion of a chemotherapeutic agent, busulfan, at embryonic day 11 (E11) induces these defects in various combinations in rat embryo limbs. In an effort to determine the mechanism by which busulfan disrupts digital development, we examined cell death by Nile Blue staining and TdT-mediated dUTP nick end labeling (TUNEL) assays; we also carried out whole mount in situ hybridization for fibroblast growth factor-8 (Fgf8), bone morphogenetic protein-4 (Bmp4), and sonic hedgehog (Shh) to examine developmental pathways linked to these defects. In busulfan-treated embryos, diffuse cell death was evident in both ectoderm and mesoderm, peaking at E13. The increased cell death leads to regression of Fgf8 in the apical ectodermal ridge (AER) and Bmp4 and Shh in the underlying mesoderm. The subsequent pattern of interdigital apoptosis and cartilage condensation was variably disrupted. These results suggest that busulfan manifests its teratogenic effects by inducing cell death of both ectoderm and mesoderm, with an associated reduction in tissue and a disruption in the generation of patterning molecules during critical periods of digit specification. [source] Sef is synexpressed with FGFs during chick embryogenesis and its expression is differentially regulated by FGFs in the developing limbDEVELOPMENTAL DYNAMICS, Issue 2 2005Haggar Harduf Abstract The signaling pathways leading to growth and patterning of various organs are tightly controlled during the development of any organism. These control mechanisms usually involve the utilization of feedback- and pathway-specific antagonists where the pathway induces the expression of its own antagonist. Sef is a feedback antagonist of fibroblast growth factor (FGF) signaling, which has been identified recently in zebrafish and mammals. Here, we report the isolation of chicken Sef (cSef) and demonstrate the conserved nature of the regulatory relationship with FGF signaling. In chick embryos, Sef is expressed in a pattern that coincides with many known sites of FGF signaling. In the developing limb, cSef is expressed in the mesoderm underlying the apical ectodermal ridge (AER) in the region known as the progress zone. cSef message first appeared after limb budding and AER formation. Expression was intense at stages of rapid limb outgrowth, and gradually decreased to almost undetectable levels when differentiation was clearly apparent. Gain- and loss-of-function experiments showed that FGFs differentially regulate the expression of cSef in various tissues. Thus, removal of the AER down-regulated cSef expression, and FGF2 but not FGF4 or FGF8 beads substituted for the AER in maintaining cSef expression. At sites where cSef is not normally expressed, FGF4 and FGF2, but not FGF8 beads, induced cSef expression. Our results demonstrate the complexity of cSef regulation by FGFs and point to FGF2 as a prime candidate in regulating cSef expression during normal limb development. The spatiotemporal pattern of cSef expression during limb development suggests a role for cSef in regulating limb outgrowth but not limb initiation. Developmental Dynamics 233:301,312, 2005. © 2005 Wiley-Liss, Inc. [source] Loss of the Tg737 protein results in skeletal patterning defectsDEVELOPMENTAL DYNAMICS, Issue 1 2003Qihong Zhang Abstract Tg737 mutant mice exhibit pathologic conditions in numerous tissues along with skeletal patterning defects. Herein, we characterize the skeletal pathologic conditions and confirm a role for Tg737 in skeletal patterning through transgenic rescue. Analyses were conducted in both the hypomorphic Tg737orpk allele that results in duplication of digit one and in the null Tg737,2-3,Gal allele that is an embryonic lethal mutation exhibiting eight digits per limb. In early limb buds, Tg737 expression is detected throughout the mesenchyme becoming concentrated in precartilage condensations at later stages. In situ analyses indicate that the Tg737orpk mutant limb defects are not associated with changes in expression of Shh, Ihh, HoxD11,13, Patched, BMPs, or Glis. Likewise, in Tg737,2-3,Gal mutant embryos, there was no change in Shh expression. However, in both alleles, Fgf4 was ectopically expressed on the anterior apical ectodermal ridge. Collectively, the data argue for a dosage effect of Tg737 on the limb phenotypes and that the polydactyly is independent of Shh misexpression. Developmental Dynamics 227:78,90, 2003. © 2003 Wiley-Liss, Inc. [source] Identification of evolutionarily conserved regulatory elements in the mouse Fgf8 locusGENESIS: THE JOURNAL OF GENETICS AND DEVELOPMENT, Issue 1 2006Friedrich Beermann Abstract The secreted signaling molecule fibroblast growth factor 8 (Fgf8) is an essential component of certain embryonic signaling centers including the mid-hindbrain (isthmic) organizer, the first branchial arch (BA1), and the apical ectodermal ridge (AER). In these signaling centers Fgf8 transcripts are expressed in a dynamic and transient fashion, but the mechanism by which this highly specific expression pattern is established remains largely unknown. We used DNA sequence comparisons coupled to transgenic approaches to obtain insight into the structure and function of regulatory elements in the Fgf8 locus. First, a bacterial artificial chromosome (BAC) containing the mouse Fgf8 gene partially rescues the embryonic lethality of Fgf8- deficient mice and controls Fgf8 -specific gene expression of a coinjected lacZ reporter transgene. Second, sequence comparison of vertebrate Fgf8 loci revealed evolutionarily highly conserved noncoding sequences that were unexpectedly located mainly 3, of the Fgf8 coding region. Third, in transgenic mice some of these elements were sufficient to target expression to the AER, tail bud, and brain, including the isthmic organizer, indicating that they may represent Fgf8 cis-acting elements. Collectively, these data identify novel regulatory elements of the Fgf8 gene sufficient to drive expression to regions of known Fgf8 activity. genesis 44:1,6, 2006. © 2006 Wiley-Liss, Inc. [source] Perspectives on hyperphalangy: patterns and processesJOURNAL OF ANATOMY, Issue 3 2004Tim J. Fedak Abstract Hyperphalangy is a digit morphology in which increased numbers of phalanges are arranged linearly within a digit beyond the plesiomorphic condition. We analyse patterns and processes of hyperphalangy by considering previous definitions and occurrences of hyperphalangy among terrestrial and secondarily aquatic extant and fossil taxa (cetaceans, ichthyosaurs, plesiosaurs and mosasaurs), and recent studies that elucidate the factors involved in terrestrial autopod joint induction. Extreme hyperphalangy, defined as exceeding a threshold condition of 4/6/6/6/6, is shown only to be found among secondarily aquatic vertebrates with a flipper limb morphology. Based on this definition, hyperphalangy occurs exclusively in digits II and III among extant cetaceans. Previous reports of cetacean embryos having more phalanges than adults is clarified and shown to be based on cartilaginous elements not ossified phalanges. Developmental prerequisites for hyperphalangy include lack of cell death in interdigital mesoderm (producing a flipper limb) and maintenance of a secondary apical ectodermal ridge (AER), which initiates digit elongation and extra joint patterning. Factors of the limb-patterning pathways located in the interdigital mesoderm, including bone morphogenetic proteins (BMPs), BMP antagonists, fibroblast growth factors (FGFs), growth/differentiation factor-5 (GDF-5), Wnt-14 and ck-erg, are implicated in maintenance of the flipper limb, secondary AER formation, digit elongation and additional joint induction leading to hyperphalangy. [source] Dynamic expression of Krüppel-like factor 4 (Klf4), a target of transcription factor AP-2, during murine mid-embryogenesisTHE ANATOMICAL RECORD : ADVANCES IN INTEGRATIVE ANATOMY AND EVOLUTIONARY BIOLOGY, Issue 2 2003Julia Ehlermann Abstract Krüppel-like factor 4 (Klf4) belongs to the family of transcription factors that are thought to be involved in the regulation of epithelial and germ cell differentiation, based on their expression in postproliferative cells of the skin, gut, and testes. Gene ablation experiments suggest that Klf4 plays a role in keratinocyte differentiation, since mice lacking Klf4 fail to establish proper barrier function and, as a consequence, die postnatally due to dehydration. Recent studies have shown that Klf4 is also expressed in postnatal male mice, in postmeiotic sperm cells undergoing terminal differentiation into sperm cells. However, prior to the current study, the expression pattern of Klf4 during early and mid-embryogenesis had not been examined. Here we demonstrate that Klf4 transcripts can be detected from embryonic day 4.5 (E4.5) on in the developing conceptus, and that Klf4 expression before E10 is restricted to extraembryonic tissues. The embryo proper displays a highly dynamic and changing Klf4 signal from E10 of murine development on. In addition to being expressed in a stripe of mesenchymal cells extending from the forelimb bud rostrally over the branchial arches to the developing eye, Klf4 is also expressed in the mesenchyme surrounding the nasal pit at day E11.5. In addition, Klf4 has been detected in the apical ectodermal ridge and adjacent mesenchymal cells in the limb buds, and in mesenchymal cells of the developing body wall in trunk areas. These findings suggest that Klf4 plays an important role in regulating cellular proliferation, which underlies the morphogenetic changes that shape the developing embryo. Anat Rec Part A 273A:677,680, 2003. © 2003 Wiley-Liss, Inc. [source] Altered localization of gene expression in both ectoderm and mesoderm is associated with a murine strain difference in retinoic acid,induced forelimb ectrodactyly,BIRTH DEFECTS RESEARCH, Issue 6 2007Hirohito Shimizu Abstract BACKGROUND: Defects in digit number or fusion as a teratogenic response are well documented in humans and intensively studied in various mouse models. Maternal exposure to excess levels of all- trans -retinoic acid (RA) at gestational day 9.5 induces postaxial ectrodactyly (digit loss) in the murine C57BL/6N strain but not in the SWV/Fnn strain. METHODS: Whole-mount in situ hybridization was used to examine the differential expression of limb patterning genes at the transcriptional level between the two mouse strains following the maternal exposure to a teratogenic level of RA. The detection of a gene with altered expression was followed by either the evaluation of other genes that were synexpressed or with an assessment of downstream genes. RESULTS: In the C57BL/6N limb bud following maternal RA administration, gene-specific perturbations were observed within hours of the RA injection in the posterior pre-AER (apical ectodermal ridge) (Fgf8, Dlx3, Bmp4, Sp8, but not Dlx2 or p63), whereas these genes were normally expressed in the SWV/Fnn limb bud. Furthermore, although RA caused comparable reductions of Shh expression between the strains in the 12 h after administration, some Shh downstream genes were differentially expressed (e.g., Gli1, Ptc, and Hoxd13), whereas others were not (e.g., Fgf4, Bmp4, and Gremlin). CONCLUSIONS: It is proposed that altered gene expression in both pre-AER and mesoderm is involved in the pathogenesis of postaxial digit loss, and that because the alterations in the pre-AER occur relatively early in the temporal sequence of events, those changes are candidates for an initiating factor in the malformation. Birth Defects Research (Part A) 2007. © 2007 Wiley-Liss, Inc. [source] Distal limb malformations: underlying mechanisms and clinical associationsCLINICAL GENETICS, Issue 3 2001S Sifakis Congenital malformations of the extremities are conspicuous and have been described through the ages. Over the past decade, a wealth of knowledge has been generated regarding the genetic regulation of limb development and the underlying molecular mechanisms. Recent studies have identified several of the signaling molecules, growth factors, and transcriptional regulators involved in the initiation and maintenance of the apical ectodermal ridge (AER) as well as the molecular markers defining the three axes of the developing limb. Studies of abnormal murine phenotypes have uncovered the role played by genes such as p63 and Dactylin in the maintenance of AER activity. These phenotypes resemble human malformations and in this review we describe the underlying mechanisms and clinical associations of split hand/foot malformation and ectrodactyly,ectodermal dysplasia,cleft lip/palate syndrome, which have both been associated with mutations in the p63 gene. [source] Studies on epidermal growth factor receptor signaling in vertebrate limb patterningDEVELOPMENTAL DYNAMICS, Issue 2 2005Minoru Omi Abstract The epidermal growth factor receptor (EGFR) regulates multiple patterning events in Drosophila limb development, but its role in vertebrate limb morphogenesis has received little attention. The EGFR and several of its ligands are expressed in developing vertebrate limbs in manners consistent with potential patterning roles. To gain insight into functions of EGFR signaling in vertebrate limb development, we expressed a constitutively active EGFR in developing chick limbs in ovo. Expression of activated EGFR causes pre- and postaxial polydactyly, including mirror-image,type digit duplication, likely due to induction of ectopic expression and/or modulation of genes involved in anterior,posterior (AP) patterning such as Sonic hedgehog (Shh), dHand, Patched (Ptc), Gli3, Hoxd13, Hoxd11, bone morphogenetic protein 2 (Bmp2), Gremlin, and FGF4. Activation of EGFR signaling dorsalizes the limb and alters expression of the dorsal,ventral (DV) patterning genes Wnt7a, Lmx, and En1. Ectopic and/or extended FGF8 expressing apical ectodermal ridges (AERs) are also seen. Interdigital regression is inhibited and the digits fail to separate, leading to syndactyly, likely due to antiapoptotic and pro-proliferative effects of activated EGFR signaling on limb mesoderm, and/or attenuation of interdigital Bmp4 expression. These findings suggest potential roles for EGFR signaling in AP and DV patterning, AER formation, and cell survival during limb morphogenesis. Developmental Dynamics 233:288,300, 2005. © 2005 Wiley-Liss, Inc. [source] | ||||||||||