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Disrupting Foxh1-Groucho interaction reveals robustness of nodal-based embryonic patterning.
Halstead AM, Wright CV
(2015) Mech Dev 136: 155-65
MeSH Terms: Animals, Body Patterning, Embryonic Development, Forkhead Transcription Factors, Gastrulation, Gene Expression Regulation, Developmental, Mice, Nodal Protein, Transcription Factors
Show Abstract · Added January 12, 2015
The winged-helix transcription factor Foxh1 is an essential regulator of Nodal signaling during the key developmental processes of gastrulation, anterior-posterior (A-P) patterning, and the derivation of left-right (L-R) asymmetry. Current models have Foxh1 bound to phospho-Smad2/3 (pSmad2/3) as a central transcriptional activator for genes targeted by Nodal signaling including Nodal itself, the feedback inhibitor Lefty2, and the positive transcriptional effector Pitx2. However, the conserved Engrailed homology-1 (EH1) motif present in Foxh1 suggests that modulated interaction with Groucho (Grg) co-repressors would allow Foxh1 to function as a transcriptional switch, toggling between transcriptional on and off states via pSmad2-Grg protein-switching, to ensure the properly timed initiation and suppression, and/or amplitude, of expression of Nodal and its target genes. We minimally mutated the Foxh1 EH1 motif, creating a novel Foxh1(mEH1) allele to test directly the contribution of Foxh1-Grg-mediated repression on the transient, dynamic pattern of Nodal signaling in mice. All aspects of Nodal and its target gene expression in Foxh1(mEH1/mEH1) embryos were equivalent to wild type. A-P patterning and organ situs in homozygous embryos and adult mice were also unaffected. The finding that Foxh1-Grg-mediated repression is not essential for Nodal expression during mouse embryogenesis suggests that other regulators compensate for the loss of repressive regulatory input that is mediated by Grg interactions. We suggest that the pervasive inductive properties of Nodal signaling exist within the context of a strongly buffered regulatory system that contributes to resilience and accuracy of its dynamic expression pattern.
Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.
2 Communities
1 Members
0 Resources
9 MeSH Terms
Tfap2a and Foxd3 regulate early steps in the development of the neural crest progenitor population.
Wang WD, Melville DB, Montero-Balaguer M, Hatzopoulos AK, Knapik EW
(2011) Dev Biol 360: 173-85
MeSH Terms: Animals, Base Sequence, Body Patterning, Bone Morphogenetic Proteins, Cell Death, DNA Primers, Embryonic Stem Cells, Forkhead Transcription Factors, Gastrulation, Gene Expression Regulation, Developmental, Genes, p53, Intercellular Signaling Peptides and Proteins, Mutation, Neural Crest, Neurogenesis, Transcription Factor AP-2, Wnt Signaling Pathway, Zebrafish, Zebrafish Proteins
Show Abstract · Added November 13, 2012
The neural crest is a stem cell-like population exclusive to vertebrates that gives rise to many different cell types including chondrocytes, neurons and melanocytes. Arising from the neural plate border at the intersection of Wnt and Bmp signaling pathways, the complexity of neural crest gene regulatory networks has made the earliest steps of induction difficult to elucidate. Here, we report that tfap2a and foxd3 participate in neural crest induction and are necessary and sufficient for this process to proceed. Double mutant tfap2a (mont blanc, mob) and foxd3 (mother superior, mos) mob;mos zebrafish embryos completely lack all neural crest-derived tissues. Moreover, tfap2a and foxd3 are expressed during gastrulation prior to neural crest induction in distinct, complementary, domains; tfap2a is expressed in the ventral non-neural ectoderm and foxd3 in the dorsal mesendoderm and ectoderm. We further show that Bmp signaling is expanded in mob;mos embryos while expression of dkk1, a Wnt signaling inhibitor, is increased and canonical Wnt targets are suppressed. These changes in Bmp and Wnt signaling result in specific perturbations of neural crest induction rather than general defects in neural plate border or dorso-ventral patterning. foxd3 overexpression, on the other hand, enhances the ability of tfap2a to ectopically induce neural crest around the neural plate, overriding the normal neural plate border limit of the early neural crest territory. Although loss of either Tfap2a or Foxd3 alters Bmp and Wnt signaling patterns, only their combined inactivation sufficiently alters these signaling gradients to abort neural crest induction. Collectively, our results indicate that tfap2a and foxd3, in addition to their respective roles in the differentiation of neural crest derivatives, also jointly maintain the balance of Bmp and Wnt signaling in order to delineate the neural crest induction domain.
Copyright © 2011 Elsevier Inc. All rights reserved.
2 Communities
2 Members
0 Resources
19 MeSH Terms
Video force microscopy reveals the mechanics of ventral furrow invagination in Drosophila.
Brodland GW, Conte V, Cranston PG, Veldhuis J, Narasimhan S, Hutson MS, Jacinto A, Ulrich F, Baum B, Miodownik M
(2010) Proc Natl Acad Sci U S A 107: 22111-6
MeSH Terms: Animals, Cytoplasm, Drosophila melanogaster, Gastrula, Microscopy, Video, Mutation, Viscosity
Show Abstract · Added May 20, 2014
The absence of tools for mapping the forces that drive morphogenetic movements in embryos has impeded our understanding of animal development. Here we describe a unique approach, video force microscopy (VFM), that allows detailed, dynamic force maps to be produced from time-lapse images. The forces at work in an embryo are considered to be decomposed into active and passive elements, where active forces originate from contributions (e.g., actomyosin contraction) that do mechanical work to the system and passive ones (e.g., viscous cytoplasm) that dissipate energy. In the present analysis, the effects of all passive components are considered to be subsumed by an effective cytoplasmic viscosity, and the driving forces are resolved into equivalent forces along the edges of the polygonal boundaries into which the region of interest is divided. Advanced mathematical inverse methods are used to determine these driving forces. When applied to multiphoton sections of wild-type and mutant Drosophila melanogaster embryos, VFM is able to calculate the equivalent driving forces acting along individual cell edges and to do so with subminute temporal resolution. In the wild type, forces along the apical surface of the presumptive mesoderm are found to be large and to vary parabolically with time and angular position, whereas forces along the basal surface of the ectoderm, for example, are found to be smaller and nearly uniform with position. VFM shows that in mutants with reduced junction integrity and myosin II activity, the driving forces are reduced, thus accounting for ventral furrow failure.
0 Communities
1 Members
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7 MeSH Terms
BMP antagonism protects Nodal signaling in the gastrula to promote the tissue interactions underlying mammalian forebrain and craniofacial patterning.
Yang YP, Anderson RM, Klingensmith J
(2010) Hum Mol Genet 19: 3030-42
MeSH Terms: Animals, Biomarkers, Body Patterning, Bone Morphogenetic Proteins, Embryo, Mammalian, Endoderm, Extracellular Space, Gastrula, Gene Expression Regulation, Developmental, Holoprosencephaly, Mice, Mice, Mutant Strains, Models, Biological, Nodal Protein, Primitive Streak, Prosencephalon, Protein Binding, Protein Multimerization, Signal Transduction
Show Abstract · Added August 28, 2017
Holoprosencephaly (HPE) is the most common forebrain and craniofacial malformation syndrome in humans. The genetics of HPE suggest that it often stems from a synergistic interaction of mutations in independent loci. In mice, several combinations of mutations in Nodal signaling pathway components can give rise to HPE, but it is not clear whether modest deficits of Nodal signaling along with lesions in other pathways might also cause such defects. We find that HPE results from simultaneous reduction of Nodal signaling and an organizer BMP (bone morphogenetic protein) antagonist, either Chordin or Noggin. These defects result from reduced production of tissues that promote forebrain and craniofacial development. Nodal promotes the expression of genes in the anterior primitive streak that are important for the development of these tissues, whereas BMP inhibits their expression. Pharmacological and transgenic manipulation of these signaling pathways suggests that BMP and Nodal antagonize each other prior to intracellular signal transduction. Biochemical experiments in vitro indicate that secreted Bmp2 and Nodal can form extracellular complexes, potentially interfering with receptor activation. Our results reveal that the patterning of forebrain and medial craniofacial elements requires a fine balance between BMP and Nodal signaling during primitive streak development, and provide a potential mechanistic basis for a new multigenic model of HPE.
0 Communities
1 Members
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19 MeSH Terms
Voltage-gated sodium channels are required for heart development in zebrafish.
Chopra SS, Stroud DM, Watanabe H, Bennett JS, Burns CG, Wells KS, Yang T, Zhong TP, Roden DM
(2010) Circ Res 106: 1342-50
MeSH Terms: Age Factors, Amino Acid Sequence, Animals, Animals, Genetically Modified, Basic Helix-Loop-Helix Transcription Factors, CHO Cells, Cell Differentiation, Cricetinae, Cricetulus, GATA Transcription Factors, Gastrulation, Gene Expression Regulation, Developmental, Gene Knockdown Techniques, Genotype, Heart, Heart Defects, Congenital, Homeobox Protein Nkx-2.5, Membrane Potentials, Molecular Sequence Data, Morphogenesis, Myocardium, NAV1.5 Voltage-Gated Sodium Channel, Oligonucleotides, Antisense, Phenotype, RNA, Messenger, Sodium Channels, Transcription Factors, Transfection, Zebrafish, Zebrafish Proteins
Show Abstract · Added January 17, 2014
RATIONALE - Voltage-gated sodium channels initiate action potentials in excitable tissues. Mice in which Scn5A (the predominant sodium channel gene in heart) has been knocked out die early in development with cardiac malformations by mechanisms which have yet to be determined.
OBJECTIVE - Here we addressed this question by investigating the role of cardiac sodium channels in zebrafish heart development.
METHODS AND RESULTS - Transcripts of the functionally-conserved Scn5a homologs scn5Laa and scn5Lab were detected in the gastrulating zebrafish embryo and subsequently in the embryonic myocardium. Antisense knockdown of either channel resulted in marked cardiac chamber dysmorphogenesis and perturbed looping. These abnormalities were associated with decreased expression of the myocardial precursor genes nkx2.5, gata4, and hand2 in anterior lateral mesoderm and significant deficits in the production of cardiomyocyte progenitors. These early defects did not appear to result from altered membrane electrophysiology, as prolonged pharmacological blockade of sodium current failed to phenocopy channel knockdown. Moreover, embryos grown in calcium channel blocker-containing medium had hearts that did not beat but developed normally.
CONCLUSIONS - These findings identify a novel and possibly nonelectrogenic role for cardiac sodium channels in heart development.
0 Communities
2 Members
0 Resources
30 MeSH Terms
Prostaglandin Gbetagamma signaling stimulates gastrulation movements by limiting cell adhesion through Snai1a stabilization.
Speirs CK, Jernigan KK, Kim SH, Cha YI, Lin F, Sepich DS, DuBois RN, Lee E, Solnica-Krezel L
(2010) Development 137: 1327-37
MeSH Terms: Animals, Cell Adhesion, DNA Primers, Dinoprostone, Embryo, Nonmammalian, Gastrula, Gastrulation, In Situ Hybridization, Prostaglandins G, RNA, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 24, 2013
Gastrulation movements form the germ layers and shape them into the vertebrate body. Gastrulation entails a variety of cell behaviors, including directed cell migration and cell delamination, which are also involved in other physiological and pathological processes, such as cancer metastasis. Decreased Prostaglandin E(2) (PGE(2)) synthesis due to interference with the Cyclooxygenase (Cox) and Prostaglandin E synthase (Ptges) enzymes halts gastrulation and limits cancer cell invasiveness, but how PGE(2) regulates cell motility remains unclear. Here we show that PGE(2)-deficient zebrafish embryos, impaired in the epiboly, internalization, convergence and extension gastrulation movements, exhibit markedly increased cell-cell adhesion, which contributes to defective cell movements in the gastrula. Our analyses reveal that PGE(2) promotes cell protrusive activity and limits cell adhesion by modulating E-cadherin transcript and protein, in part through stabilization of the Snai1a (also known as Snail1) transcriptional repressor, an evolutionarily conserved regulator of cell delamination and directed migration. We delineate a pathway whereby PGE(2) potentiates interaction between the receptor-coupled G protein betagamma subunits and Gsk3beta to inhibit proteasomal degradation of Snai1a. However, overexpression of beta-catenin cannot stabilize Snai1a in PGE(2)-deficient gastrulae. Thus, the Gsk3beta-mediated and beta-catenin-independent inhibition of cell adhesion by Prostaglandins provides an additional mechanism for the functional interactions between the PGE(2) and Wnt signaling pathways during development and disease. We propose that ubiquitously expressed PGE(2) synthesizing enzymes, by promoting the stability of Snai1a, enable the precise and rapid regulation of cell adhesion that is required for the dynamic cell behaviors that drive various gastrulation movements.
0 Communities
2 Members
0 Resources
16 MeSH Terms
Galpha12/13 regulate epiboly by inhibiting E-cadherin activity and modulating the actin cytoskeleton.
Lin F, Chen S, Sepich DS, Panizzi JR, Clendenon SG, Marrs JA, Hamm HE, Solnica-Krezel L
(2009) J Cell Biol 184: 909-21
MeSH Terms: Actins, Animals, Cadherins, Cell Adhesion, Cell Movement, Cytoskeleton, GTP-Binding Protein alpha Subunits, G12-G13, Gastrula, Gastrulation, Gene Expression Regulation, Developmental, Guanine Nucleotide Exchange Factors, Mutation, Protein Structure, Tertiary, Recombinant Fusion Proteins, Signal Transduction, Time Factors, Zebrafish, Zebrafish Proteins, rho GTP-Binding Proteins
Show Abstract · Added December 10, 2013
Epiboly spreads and thins the blastoderm over the yolk cell during zebrafish gastrulation, and involves coordinated movements of several cell layers. Although recent studies have begun to elucidate the processes that underlie these epibolic movements, the cellular and molecular mechanisms involved remain to be fully defined. Here, we show that gastrulae with altered Galpha(12/13) signaling display delayed epibolic movement of the deep cells, abnormal movement of dorsal forerunner cells, and dissociation of cells from the blastoderm, phenocopying e-cadherin mutants. Biochemical and genetic studies indicate that Galpha(12/13) regulate epiboly, in part by associating with the cytoplasmic terminus of E-cadherin, and thereby inhibiting E-cadherin activity and cell adhesion. Furthermore, we demonstrate that Galpha(12/13) modulate epibolic movements of the enveloping layer by regulating actin cytoskeleton organization through a RhoGEF/Rho-dependent pathway. These results provide the first in vivo evidence that Galpha(12/13) regulate epiboly through two distinct mechanisms: limiting E-cadherin activity and modulating the organization of the actin cytoskeleton.
0 Communities
1 Members
0 Resources
19 MeSH Terms
Lrp6 is required for convergent extension during Xenopus gastrulation.
Tahinci E, Thorne CA, Franklin JL, Salic A, Christian KM, Lee LA, Coffey RJ, Lee E
(2007) Development 134: 4095-106
MeSH Terms: Amino Acid Sequence, Animals, Animals, Genetically Modified, Body Patterning, Cell Polarity, Cells, Cultured, Embryo, Nonmammalian, Gastrulation, Gene Expression Regulation, Developmental, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Mesoderm, Models, Biological, Molecular Sequence Data, Receptors, LDL, Sequence Homology, Amino Acid, Signal Transduction, Tissue Distribution, Wnt Proteins, Xenopus, beta Catenin
Show Abstract · Added August 12, 2010
Wnt signaling regulates beta-catenin-mediated gene transcription and planar cell polarity (PCP). The Wnt co-receptor, Lrp6, is required for signaling along the beta-catenin arm. We show that Lrp6 downregulation (by morpholino injection) or overexpression in Xenopus embryos disrupts convergent extension, a hallmark feature of Wnt/PCP components. In embryos with decreased Lrp6 levels, cells of the dorsal marginal zone (DMZ), which undergoes extensive cellular rearrangements during gastrulation, exhibit decreased length:width ratios, decreased migration, and increased numbers of transient cytoplasmic protrusions. We show that Lrp6 opposes Wnt11 activity and localizes to the posterior edge of migrating DMZ cells and that Lrp6 downregulation enhances cortical and nuclear localization of Dsh and phospho-JNK, respectively. Taken together, these data suggest that Lrp6 inhibits Wnt/PCP signaling. Finally, we identify the region of the Lrp6 protein with Wnt/PCP activity to a stretch of 36 amino acids, distinct from regions required for Wnt/beta-catenin signaling. We propose a model in which Lrp6 plays a critical role in the switch from Wnt/PCP to Wnt/beta-catenin signaling.
1 Communities
4 Members
0 Resources
21 MeSH Terms
Eye field requires the function of Sfrp1 as a Wnt antagonist.
Kim HS, Shin J, Kim SH, Chun HS, Kim JD, Kim YS, Kim MJ, Rhee M, Yeo SY, Huh TL
(2007) Neurosci Lett 414: 26-9
MeSH Terms: Animals, Body Patterning, Cytoskeletal Proteins, Eye, Eye Abnormalities, Gastrula, Gene Expression Regulation, Developmental, Intercellular Signaling Peptides and Proteins, Lithium Chloride, Mesencephalon, Nervous System Malformations, Organogenesis, PAX2 Transcription Factor, Prosencephalon, Signal Transduction, Visual Pathways, Wnt Proteins, Zebrafish, Zebrafish Proteins
Show Abstract · Added September 24, 2013
Wnts have been shown to provide a posteriorizing signal that has to be repressed in the specification of vertebrate forebrain region. Previous studies have shown that Wnt activation by LiCl treatment causes an expansion of optic stalk and mid-hindbrain boundary, whereas eye and ventral diencephalon in the forebrain region were reduced. However, the molecular mechanism, by which inhibits Wnt activity in the forebrain remains poorly defined. To investigate relationship between forebrain specification and Wnt signaling, the zebrafish homologue of secreted frizzled related protein1 (sfrp1) has been characterized. The transcripts of sfrp1 are detected in the presumptive forebrain at gastrula and in the ventral telencephalon, ventral diencephalon, midbrain and optic vesicles at 24h after postfertilization (hpf). Overexpression of sfrp1 causes an anteriorization of embryo, with enlarged head and reduced posterior structure as in the embryo overexpressing dominant-negative form of Frizzled8a or Dkk1. Its overexpression restored the eye defects in the Wnt8b-overexpressing embryos, but not in the LiCl-treated embryos. These results suggest that Sfrp1 expressed in the forebrain and eye field plays a critical role in the extracellular events of antagonizing Wnt activity for the forebrain specification.
0 Communities
1 Members
0 Resources
19 MeSH Terms
FoxD3 regulation of Nodal in the Spemann organizer is essential for Xenopus dorsal mesoderm development.
Steiner AB, Engleka MJ, Lu Q, Piwarzyk EC, Yaklichkin S, Lefebvre JL, Walters JW, Pineda-Salgado L, Labosky PA, Kessler DS
(2006) Development 133: 4827-38
MeSH Terms: Animals, Body Patterning, Chordata, Embryonic Induction, Forkhead Transcription Factors, Gastrula, Gene Expression Regulation, Developmental, Homeodomain Proteins, Mesoderm, Nodal Protein, Organizers, Embryonic, Repressor Proteins, Signal Transduction, Transforming Growth Factor beta, Xenopus Proteins, Xenopus laevis
Show Abstract · Added July 20, 2010
Induction and patterning of the mesodermal germ layer is a key early step of vertebrate embryogenesis. We report that FoxD3 function in the Xenopus gastrula is essential for dorsal mesodermal development and for Nodal expression in the Spemann organizer. In embryos and explants, FoxD3 induced mesodermal genes, convergent extension movements and differentiation of axial tissues. Engrailed-FoxD3, but not VP16-FoxD3, was identical to native FoxD3 in mesoderm-inducing activity, indicating that FoxD3 functions as a transcriptional repressor to induce mesoderm. Antagonism of FoxD3 with VP16-FoxD3 or morpholino-knockdown of FoxD3 protein resulted in a complete block to axis formation, a loss of mesodermal gene expression, and an absence of axial mesoderm, indicating that transcriptional repression by FoxD3 is required for mesodermal development. FoxD3 induced mesoderm in a non-cell-autonomous manner, indicating a role for secreted inducing factors in the response to FoxD3. Consistent with this mechanism, FoxD3 was necessary and sufficient for the expression of multiple Nodal-related genes, and inhibitors of Nodal signaling blocked mesoderm induction by FoxD3. Therefore, FoxD3 is required for Nodal expression in the Spemann organizer and this function is essential for dorsal mesoderm formation.
1 Communities
1 Members
0 Resources
16 MeSH Terms