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1: Development. 2006 May;133(9):1657-71. Epub 2006 Mar 22.Click here to read Links

Early, H+-V-ATPase-dependent proton flux is necessary for consistent left-right patterning of non-mammalian vertebrates.

Adams DS, Robinson KR, Fukumoto T, Yuan S, Albertson RC, Yelick P, Kuo L, McSweeney M, Levin M.

The Forsyth Center for Regenerative and Developmental Biology, and Department of Developmental Biology, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA 02115, USA.

Biased left-right asymmetry is a fascinating and medically important phenomenon. We provide molecular genetic and physiological characterization of a novel, conserved, early, biophysical event that is crucial for correct asymmetry: H+ flux. A pharmacological screen implicated the H+-pump H+-V-ATPase in Xenopus asymmetry, where it acts upstream of early asymmetric markers. Immunohistochemistry revealed an actin-dependent asymmetry of H+-V-ATPase subunits during the first three cleavages. H+-flux across plasma membranes is also asymmetric at the four- and eight-cell stages, and this asymmetry requires H+-V-ATPase activity. Abolishing the asymmetry in H+ flux, using a dominant-negative subunit of the H+-V-ATPase or an ectopic H+ pump, randomized embryonic situs without causing any other defects. To understand the mechanism of action of H+-V-ATPase, we isolated its two physiological functions, cytoplasmic pH and membrane voltage (Vmem) regulation. Varying either pH or Vmem, independently of direct manipulation of H+-V-ATPase, caused disruptions of normal asymmetry, suggesting roles for both functions. V-ATPase inhibition also abolished the normal early localization of serotonin, functionally linking these two early asymmetry pathways. The involvement of H+-V-ATPase in asymmetry is conserved to chick and zebrafish. Inhibition of the H+-V-ATPase induces heterotaxia in both species; in chick, H+-V-ATPase activity is upstream of Shh; in fish, it is upstream of Kupffer's vesicle and Spaw expression. Our data implicate H+-V-ATPase activity in patterning the LR axis of vertebrates and reveal mechanisms upstream and downstream of its activity. We propose a pH- and Vmem-dependent model of the early physiology of LR patterning.

PMID: 16554361 [PubMed - indexed for MEDLINE]

2: Development. 2003 Jun;130(11):2303-16.Click here to read Links

The zebrafish nodal-related gene southpaw is required for visceral and diencephalic left-right asymmetry.

Long S, Ahmad N, Rebagliati M.

Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA 52242, USA.

We have identified and characterized a new zebrafish gene, southpaw, that is required for visceral and diencephalic left-right asymmetry. southpaw encodes a new member of the nodal-related class of proteins, a subfamily within the transforming growth factor beta superfamily of secreted factors. southpaw is expressed bilaterally in paraxial mesoderm precursors and then within the left lateral plate mesoderm. At late somite stages, left-sided southpaw expression transiently overlaps the left-sided expression domains of other genes that mark the developing heart, such as lefty2. We have injected morpholinos to block the translation of the southpaw mRNA or to block splicing of the southpaw pre-mRNA. These morpholinos cause a severe disruption of early (cardiac jogging) and late (cardiac looping) aspects of cardiac left-right asymmetry. As the left-right asymmetry of the pancreas is also affected, southpaw appears to regulate left-right asymmetry throughout a large part of the embryo. Consistent with the morphological changes, the left-sided expression domains of downstream genes (cyclops, pitx2, lefty1 and lefty2) are severely downregulated or abolished within the lateral plate mesoderm of Southpaw-deficient embryos. Surprisingly, despite the absence of southpaw expression in the brain, we find that early diencephalic left-right asymmetry also requires Southpaw activity. These observations lead to a model of how visceral organ and brain left-right asymmetry are coordinated during embryogenesis.

PMID: 12702646 [PubMed - indexed for MEDLINE]

3: Dev Biol. 2005 Jul 15;283(2):310-21.Click here to read Links

Roles for fgf8 signaling in left-right patterning of the visceral organs and craniofacial skeleton.

Albertson RC, Yelick PC.

Department of Cytokine Biology, The Forsyth Institute, Harvard School of Dental Medicine, Boston, MA 02115, USA. calbertson@forsyth.org

Laterality is fundamental to the vertebrate body plan. Here, we investigate the roles of fgf8 signaling in LR patterning of the zebrafish embryo. We find that fgf8 is required for proper asymmetric development of the brain, heart and gut. When fgf8 is absent, nodal signaling is randomized in the lateral plate mesoderm, leading to aberrant LR orientation of the brain and visceral organs. We also show that fgf8 is necessary for proper symmetric development of the pharyngeal skeleton. Attenuated fgf8 signaling results in consistently biased LR asymmetric development of the pharyngeal arches and craniofacial skeleton. Approximately 1/3 of zebrafish ace/fgf8 mutants are missing Kupffer's vesicle (KV), a ciliated structure similar to Hensen's node. We correlate fgf8 deficient laterality defects in the brain and viscera with the absence of KV, supporting a role for KV in proper LR patterning of these structures. Strikingly, we also correlate asymmetric craniofacial development in ace/fgf8 mutants with the presence of KV, suggesting roles for KV in lateralization of the pharyngeal skeleton when fgf8 is absent. These data provide new insights into vertebrate laterality and offer the zebrafish ace/fgf8 mutant as a novel molecular tool to investigate tissue-specific molecular laterality mechanisms.

PMID: 15932752 [PubMed - indexed for MEDLINE]

4: Dev Biol. 2005 Nov 15;287(2):274-88. Epub 2005 Oct 7.Click here to read Links

Polaris and Polycystin-2 in dorsal forerunner cells and Kupffer's vesicle are required for specification of the zebrafish left-right axis.

Bisgrove BW, Snarr BS, Emrazian A, Yost HJ.

Huntsman Cancer Institute Center for Children, Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112, USA.

Recently, it has become clear that motile cilia play a central role in initiating a left-sided signaling cascade important in establishing the LR axis during mouse and zebrafish embryogenesis. Two genes proposed to be important in this cilia-mediated signaling cascade are polaris and polycystin-2 (pkd2). Polaris is involved in ciliary assembly, while Pkd2 is proposed to function as a Ca(2+)-permeable cation channel. We have cloned zebrafish homologues of polaris and pkd2. Both genes are expressed in dorsal forerunner cells (DFCs) from gastrulation to early somite stages when these cells form a ciliated Kupffer's vesicle (KV). Morpholino-mediated knockdown of Polaris or Pkd2 in zebrafish results in misexpression of left-side-specific genes, including southpaw, lefty1 and lefty2, and randomization of heart and gut looping. By targeting morpholinos to DFCs/KV, we show that polaris and pkd2 are required in DFCs/KV for normal LR development. Polaris morphants have defects in KV cilia, suggesting that the laterality phenotype is due to problems in cilia function per se. We further show that expression of polaris and pkd2 is dependent on the T-box transcription factors no tail and spadetail, respectively, suggesting that these genes have a previously unrecognized role in regulating ciliary structure and function. Our data suggest that the functions of polaris and pkd2 in LR patterning are conserved between zebrafish and mice and that Kupffer's vesicle functions as a ciliated organ of asymmetry.

PMID: 16216239 [PubMed - indexed for MEDLINE]

5: Development. 2005 Nov;132(21):4869-81. Epub 2005 Oct 5.Click here to read Links

Directional asymmetry of the zebrafish epithalamus guides dorsoventral innervation of the midbrain target.

Gamse JT, Kuan YS, Macurak M, Brösamle C, Thisse B, Thisse C, Halpern ME.

Carnegie Institution of Washington, Department of Embryology, Baltimore, MD 21218, USA.

The zebrafish epithalamus, consisting of the pineal complex and flanking dorsal habenular nuclei, provides a valuable model for exploring how left-right differences could arise in the vertebrate brain. The parapineal lies to the left of the pineal and the left habenula is larger, has expanded dense neuropil, and distinct patterns of gene expression from the right habenula. Under the influence of Nodal signaling, positioning of the parapineal sets the direction of habenular asymmetry and thereby determines the left-right origin of habenular projections onto the midbrain target, the interpeduncular nucleus (IPN). In zebrafish with parapineal reversal, neurons from the left habenula project to a more limited ventral IPN region where right habenular axons would normally project. Conversely, efferents from the right habenula adopt a more extensive dorsoventral IPN projection pattern typical of left habenular neurons. Three members of the leftover-related KCTD (potassium channel tetramerization domain containing) gene family are expressed differently by the left and right habenula, in patterns that define asymmetric subnuclei. Molecular asymmetry extends to protein levels in habenular efferents, providing additional evidence that left and right axons terminate within different dorsoventral regions of the midbrain target. Laser-mediated ablation of the parapineal disrupts habenular asymmetry and consequently alters the dorsoventral distribution of innervating axons. The results demonstrate that laterality of the dorsal forebrain influences the formation of midbrain connections and their molecular properties.

PMID: 16207761 [PubMed - indexed for MEDLINE]

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  • Potassium (Glu-K® , K+ 10® , K+ 8® , ...)

    Potassium is essential for the proper functioning of the heart, kidneys, muscles, nerves, and digestive system. Usually the food you eat supplies all of the potassium you need. However, certain diseases (e.g., kidney dis...

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6: J Exp Zoolog B Mol Dev Evol. 2007 Sep 15;308(5):669-78.Click here to read Links

Selective asymmetry in a conserved forebrain to midbrain projection.

Kuan YS, Gamse JT, Schreiber AM, Halpern ME.

Department of Embryology, Carnegie Institution of Washington, Baltimore, Maryland 21218, USA.

How the left and right sides of the brain acquire anatomical and functional specializations is not well understood. The zebrafish has proven to be a useful model to explore the genetic basis of neuroanatomical asymmetry in the developing forebrain. The dorsal diencephalon or epithalamus consists of the asymmetric pineal complex and adjacent paired nuclei, the left and right medial habenulae, which in zebrafish larvae, exhibit differences in their size, neuropil density and patterns of gene expression. In all vertebrates, axons from the medial habenular nuclei project within a prominent fiber bundle, the fasciculus retroflexus, to a shared midbrain target, the interpeduncular nucleus of the ventral tegmentum. However, in zebrafish, projections from the left habenula innervate the dorsal and ventral regions of the target nucleus, whereas right habenular efferents project only to the ventral region. A similar dorsoventral difference in habenular connectivity is found in another teleost species, the highly derived southern flounder, Paralichthys lethostima. In this flatfish, directional asymmetry of the habenular projection appears to be independent of the left-right morphology and orientation that an individual adopts post-metamorphosis. Comparative anterograde labeling of the brains of salamanders, frogs and mice reveals that axons emanating from the left and right medial habenulae do not project to different domains, but rather, they traverse the target nucleus in a complementary mirror image pattern. Thus, although the habenulo-interpeduncular conduction system is highly conserved in the vertebrate brain, the stereotypic dorsoventral topography of left-right connections appears to be a feature that is specific to teleosts. Copyright 2007 Wiley-Liss, Inc.

PMID: 17592620 [PubMed - indexed for MEDLINE]

7: Dev Dyn. 2007 Aug;236(8):2131-46.Click here to read Links

Nodal activity around Kupffer's vesicle depends on the T-box transcription factors Notail and Spadetail and on Notch signaling.

Gourronc F, Ahmad N, Nedza N, Eggleston T, Rebagliati M.

Department of Anatomy and Cell Biology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.

The node, or its zebrafish equivalent, Kupffers Vesicle (KV), is thought to generate laterality cues through cilia-dependent signaling. An interaction between Nodal ligands and Nodal antagonists around the node/KV is also required. Here we investigate whether loss of Brachyury/Notail or Tbx16/Spadetail disrupts the balance of Nodal ligands (Southpaw) and antagonists (Charon) around Kupffers Vesicle. Reduction of Spadetail or Notail disrupts expression of southpaw in the perinodal domains flanking Kupffers Vesicle. Similar to what was published for Notail, we find Spadetail is also required for expression of charon. We present evidence for the model that Notail has a direct role in regulating the charon promoter. In particular, a flanking genomic region with putative Notail binding sites can drive KV expression of a reporter in a Notail-dependent fashion. This region also contains motifs for CSL/RBP-J/Su(H). Consistent with this, we find charon expression is strongly Notch-dependent whereas perinodal southpaw expression is not. (c) 2007 Wiley-Liss, Inc.

PMID: 17654709 [PubMed - indexed for MEDLINE]

8: Development. 2008 Jan;135(1):75-84. Epub 2007 Nov 28.Click here to read Links

Calcium fluxes in dorsal forerunner cells antagonize beta-catenin and alter left-right patterning.

Schneider I, Houston DW, Rebagliati MR, Slusarski DC.

Department of Biological Sciences, University of Iowa, Iowa City, IA 52242, USA.

Establishment of the left-right axis is essential for normal organ morphogenesis and function. Ca(2+) signaling and cilia function in the zebrafish Kuppfer's Vesicle (KV) have been implicated in laterality. Here we describe an endogenous Ca(2+) release event in the region of the KV precursors (dorsal forerunner cells, DFCs), prior to KV and cilia formation. Manipulation of Ca(2+) release to disrupt this early flux does not impact early DFC specification, but results in altered DFC migration or cohesion in the tailbud at somite stages. This leads to disruption of KV formation followed by bilateral expression of asymmetrical genes, and randomized organ laterality. We identify beta-catenin inhibition as a Ca(2+)-signaling target and demonstrate that localized loss of Ca(2+) within the DFC region or DFC-specific activation of beta-catenin is sufficient to alter laterality in zebrafish. We identify a previously unknown DFC-like cell population in Xenopus and demonstrate a similar Ca(2+)-sensitive stage. As in zebrafish, manipulation of Ca(2+) release results in ectopic nuclear beta-catenin and altered laterality. Overall, our data support a conserved early Ca(2+) requirement in DFC-like cell function in zebrafish and Xenopus.

PMID: 18045845 [PubMed - indexed for MEDLINE]

9: Development. 2008 May;135(9):1693-702. Epub 2008 Apr 2.Click here to read Links

Tbx2b is required for the development of the parapineal organ.

Snelson CD, Santhakumar K, Halpern ME, Gamse JT.

Department of Biological Sciences, Vanderbilt University, VU Station B, Box 35-1634, Nashville, TN 37235, USA.

Structural differences between the left and right sides of the brain exist throughout the vertebrate lineage. By studying the zebrafish pineal complex, which exhibits notable asymmetries, both the genes and the cell movements that result in left-right differences can be characterized. The pineal complex consists of the midline pineal organ and the left-sided parapineal organ. The parapineal is responsible for instructing the asymmetric architecture of the bilateral habenulae, the brain nuclei that flank the pineal complex. Using in vivo time-lapse confocal microscopy, we find that the cells that form the parapineal organ migrate as a cluster of cells from the pineal complex anlage to the left side of the brain. In a screen for mutations that disrupted brain laterality, we identified a nonsense mutation in the T-box2b (tbx2b) gene, which encodes a transcription factor expressed in the pineal complex anlage. The tbx2b mutant makes fewer parapineal cells, and they remain as individuals near the midline rather than migrating leftward as a group. The reduced number and incorrect placement of parapineal cells result in symmetric development of the adjacent habenular nuclei. We conclude that tbx2b functions to specify the correct number of parapineal cells and to regulate their asymmetric migration.

PMID: 18385257 [PubMed - indexed for MEDLINE]

10: Dev Biol. 2007 May 15;305(2):577-88. Epub 2007 Mar 6.Click here to read Links

Zebrafish Bmp4 regulates left-right asymmetry at two distinct developmental time points.

Chocron S, Verhoeven MC, Rentzsch F, Hammerschmidt M, Bakkers J.

Cardiac Development and Genetics Group, Hubrecht Laboratory, Uppsalalaan 8, Utrecht, The Netherlands.

Left-right (LR) asymmetry is regulated by early asymmetric signals within the embryo. Even though the role of the bone morphogenetic protein (BMP) pathway in this process has been reported extensively in various model organisms, opposing models for the mechanism by which BMP signaling operates still prevail. Here we show that in zebrafish embryos there are two distinct phases during LR patterning in which BMP signaling is required. Using transgenic lines that ectopically express either noggin3 or bmp2b, we show a requirement for BMP signaling during early segmentation to repress southpaw expression in the right lateral plate mesoderm and regulate both visceral and heart laterality. A second phase was identified during late segmentation, when BMP signaling is required in the left lateral plate mesoderm to regulate left-sided gene expression and heart laterality. Using morpholino knock down experiments, we identified Bmp4 as the ligand responsible for both phases of BMP signaling. In addition, we detected bmp4 expression in Kupffer's vesicle and show that restricted knock down of bmp4 in this structure results in LR patterning defects. The identification of these two distinct and opposing activities of BMP signaling provides new insight into how BMP signaling can regulate LR patterning.

PMID: 17395172 [PubMed - indexed for MEDLINE]

11: Dev Biol. 2007 Oct 15;310(2):196-210. Epub 2007 Jun 4.Click here to read Links

Two T-box genes play independent and cooperative roles to regulate morphogenesis of ciliated Kupffer's vesicle in zebrafish.

Amack JD, Wang X, Yost HJ.

Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112, USA.

The brain, heart and gastro-intestinal tract develop distinct left-right (LR) asymmetries. Asymmetric cilia-dependent fluid flow in the embryonic node in mouse, Kupffer's vesicle in zebrafish, notochordal plate in rabbit and gastrocoel roof plate in frog appears to be a conserved mechanism that directs LR asymmetric gene expression and establishes the orientation of organ asymmetry. However, the cellular processes and genetic pathways that control the formation of these essential ciliated structures are unknown. In zebrafish, migratory dorsal forerunner cells (DFCs) give rise to Kupffer's vesicle (KV), a ciliated epithelial sheet that forms a lumen and generates fluid flow. Using the epithelial marker atypical Protein Kinase C (aPKC) and other markers to analyze DFCs and KV cells, we describe a multi-step process by which DFCs form a functional KV. Using mutants and morpholinos, we show that two T-box transcription factors-No tail (Ntl)/Brachyury and Tbx16/Spadetail-cooperatively regulate an early step of DFC mesenchyme to epithelial transition (MET) and KV cell specification. Subsequently, each transcription factor independently controls a distinct step in KV formation: Tbx16 regulates apical clustering of KV cells and Ntl is necessary for KV lumen formation. By targeting morpholinos to DFCs, we show that these cell autonomous functions in KV morphogenesis are necessary for LR patterning throughout the embryo.

PMID: 17765888 [PubMed - indexed for MEDLINE]

12: Development. 2004 Apr;131(8):1741-53.Click here to read Links

The Cerberus/Dan-family protein Charon is a negative regulator of Nodal signaling during left-right patterning in zebrafish.

Hashimoto H, Rebagliati M, Ahmad N, Muraoka O, Kurokawa T, Hibi M, Suzuki T.

National Research Institute of Aquaculture, Nansei, Mie 516-0193, Japan.

We have isolated a novel gene, charon, that encodes a member of the Cerberus/Dan family of secreted factors. In zebrafish, Fugu and flounder, charon is expressed in regions embracing Kupffer's vesicle, which is considered to be the teleost fish equivalent to the region of the mouse definitive node that is required for left-right (L/R) patterning. Misexpression of Charon elicited phenotypes similar to those of mutant embryos defective in Nodal signaling or embryos overexpressing Antivin(Atv)/Lefty1, an inhibitor for Nodal and Activin. Charon also suppressed the dorsalizing activity of all three of the known zebrafish Nodal-related proteins (Cyclops, Squint and Southpaw), indicating that Charon can antagonize Nodal signaling. Because Southpaw functions in the L/R patterning of lateral plate mesoderm and the diencephalon, we asked whether Charon is involved in regulating L/R asymmetry. Inhibition of Charon's function by antisense morpholino oligonucleotides (MOs) led to a loss of L/R polarity, as evidenced by bilateral expression of the left side-specific genes in the lateral plate mesoderm (southpaw, cyclops, atv/lefty1, lefty2 and pitx2) and diencephalon (cyclops, atv/lefty1 and pitx2), and defects in early (heart jogging) and late (heart looping) asymmetric heart development, but did not disturb the notochord development or the atv/lefty1-mediated midline barrier function. MO-mediated inhibition of both Charon and Southpaw led to a reduction in or loss of the expression of the left side-specific genes, suggesting that Southpaw is epistatic to Charon in left-side formation. These data indicate that antagonistic interactions between Charon and Nodal (Southpaw), which take place in regions adjacent to Kupffer's vesicle, play an important role in L/R patterning in zebrafish.

PMID: 15084459 [PubMed - indexed for MEDLINE]

13: Hum Mol Genet. 2006 Nov 15;15(22):3369-77. Epub 2006 Oct 12.Click here to read Links

Sesn1 is a novel gene for left-right asymmetry and mediating nodal signaling.

Peeters H, Voz ML, Verschueren K, De Cat B, Pendeville H, Thienpont B, Schellens A, Belmont JW, David G, Van De Ven WJ, Fryns JP, Gewillig M, Huylebroeck D, Peers B, Devriendt K.

Department of Human Genetics, Clinical Genetics Unit, University of Leuven, Belgium. hilde.peeters@uz.kuleuven.ac.be

Remarkable progress has been made in understanding the molecular mechanisms underlying left-right asymmetry in vertebrate animal models but little is known on left-right axis formation in humans. Previously, we identified SESN1 (also known as PA26) as a candidate gene for heterotaxia by positional cloning of the breakpoint regions of a de novo translocation in a heterotaxia patient. In this study, we show by means of a zebrafish sesn1-knockdown model that Sesn1 is required for normal embryonic left-right determination. In this model, developmental defects and expression data of genes implicated in vertebrate left-right asymmetry indicate a role for Sesn1 in mediating Nodal signaling. In the lateral plate mesoderm, Nodal signaling plays a central role in left-right axis formation in vertebrates and is mediated by FoxH1 transcriptional induction. In line with this, we show that Sesn1 physically interacts with FoxH1 or a FoxH1-containing complex. Mutation analysis in a panel of 234 patients with isolated heterotaxia did not reveal mutations, indicating that these are only exceptional causes of human heterotaxia. In this study, we identify SESN1 as an indispensable gene for vertebrate left-right asymmetry and a new player in mediating Nodal signaling.

PMID: 17038485 [PubMed - indexed for MEDLINE]

14: Development. 2007 Mar;134(5):921-31. Epub 2007 Jan 31.Click here to read Links

New functions for a vertebrate Rho guanine nucleotide exchange factor in ciliated epithelia.

Panizzi JR, Jessen JR, Drummond IA, Solnica-Krezel L.

Department of Biological Sciences, Vanderbilt University, Nashville, TN 37235, USA.

Human ARHGEF11, a PDZ-domain-containing Rho guanine nucleotide exchange factor (RhoGEF), has been studied primarily in tissue culture, where it exhibits transforming ability, associates with and modulates the actin cytoskeleton, regulates neurite outgrowth, and mediates activation of Rho in response to stimulation by activated Galpha12/13 or Plexin B1. The fruit fly homolog, RhoGEF2, interacts with heterotrimeric G protein subunits to activate Rho, associates with microtubules, and is required during gastrulation for cell shape changes that mediate epithelial folding. Here, we report functional characterization of a zebrafish homolog of ARHGEF11 that is expressed ubiquitously at blastula and gastrula stages and is enriched in neural tissues and the pronephros during later embryogenesis. Similar to its human homolog, zebrafish Arhgef11 stimulated actin stress fiber formation in cultured cells, whereas overexpression in the embryo of either the zebrafish or human protein impaired gastrulation movements. Loss-of-function experiments utilizing a chromosomal deletion that encompasses the arhgef11 locus, and antisense morpholino oligonucleotides designed to block either translation or splicing, produced embryos with ventrally-curved axes and a number of other phenotypes associated with ciliated epithelia. Arhgef11-deficient embryos often exhibited altered expression of laterality markers, enlarged brain ventricles, kidney cysts, and an excess number of otoliths in the otic vesicles. Although cilia formed and were motile in these embryos, polarized distribution of F-actin and Na(+)/K(+)-ATPase in the pronephric ducts was disturbed. Our studies in zebrafish embryos have identified new, essential roles for this RhoGEF in ciliated epithelia during vertebrate development.

PMID: 17267448 [PubMed - indexed for MEDLINE]

Patient Drug Information

  • Potassium (Glu-K® , K+ 10® , K+ 8® , ...)

    Potassium is essential for the proper functioning of the heart, kidneys, muscles, nerves, and digestive system. Usually the food you eat supplies all of the potassium you need. However, certain diseases (e.g., kidney dis...

  • Source: AHFS Consumer Medication Information
15: Development. 2007 Apr;134(8):1605-15. Epub 2007 Mar 14.Click here to read Links

Zebrafish curly up encodes a Pkd2 ortholog that restricts left-side-specific expression of southpaw.

Schottenfeld J, Sullivan-Brown J, Burdine RD.

Department of Molecular Biology, Princeton University, Princeton, NJ 08550, USA.

The zebrafish mutation curly up (cup) affects the zebrafish ortholog of polycystic kidney disease 2, a gene that encodes the Ca(2+)-activated non-specific cation channel, Polycystin 2. We have characterized two alleles of cup, both of which display defects in organ positioning that resemble human heterotaxia, as well as abnormalities in asymmetric gene expression in the lateral plate mesoderm (LPM) and dorsal diencephalon of the brain. Interestingly, mouse and zebrafish pkd2(-/-) mutants have disparate effects on nodal expression. In the majority of cup embryos, the zebrafish nodal gene southpaw (spaw) is activated bilaterally in LPM, as opposed to the complete absence of Nodal reported in the LPM of the Pkd2-null mouse. The mouse data indicate that Pkd2 is responsible for an asymmetric calcium transient that is upstream of Nodal activation. In zebrafish, it appears that pkd2 is not responsible for the activation of spaw transcription, but is required for a mechanism to restrict spaw expression to the left half of the embryo. pkd2 also appears to play a role in the propagation of Nodal signals in the LPM. Based on morpholino studies, we propose an additional role for maternal pkd2 in general mesendoderm patterning.

PMID: 17360770 [PubMed - indexed for MEDLINE]

16: Gene Expr Patterns. 2007 Jan;7(1-2):93-101. Epub 2006 Jun 6.Click here to read Links

Dynamic expression pattern of Nodal-related genes during left-right development in medaka.

Soroldoni D, Bajoghli B, Aghaallaei N, Czerny T.

Institute of Animal Breeding and Genetics, University of Veterinary Medicine, Veterinärplatz 1, A-1210 Vienna, Austria.

Nodal-related genes have been implicated in mesendoderm induction, establishment of embryonic axes, neural patterning and left-right development among vertebrates. Here we report the isolation of three Nodal-related genes in medaka (Oryzias latipes). Based on sequence analysis and in accordance to zebrafish orthologues we named the isolated genes Ndr1, Ndr2 and Spaw. Gene expression analysis throughout medaka development confirmed this assignment. Ndr1 and Ndr2 are detectable during gastrulation whereas Ndr2 and Spaw are expressed asymmetrically during somitogenesis. In accordance with its zebrafish orthologue, Spaw is expressed as the first asymmetric marker in the left lateral plate mesoderm (LPM) and Ndr2 displays asymmetric expression domains in the brain and the LPM. In general, the spatial distribution of Nodal transcripts resembles those reported for zebrafish, in case of Ndr2, however, we report a novel left-right asymmetry in the posterior paraxial mesoderm flanking the Kupffer's vesicle.

PMID: 16831571 [PubMed - indexed for MEDLINE]

17: Nat Genet. 2006 Nov;38(11):1316-22. Epub 2006 Oct 1.Click here to read Links

Regulation of primary cilia formation and left-right patterning in zebrafish by a noncanonical Wnt signaling mediator, duboraya.

Oishi I, Kawakami Y, Raya A, Callol-Massot C, Izpisúa Belmonte JC.

Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA.

Primary cilia are microtubule-based organelles that project from the surface of nearly every animal cell. Although important functions of primary cilia in morphogenesis and tissue homeostasis have been identified, the mechanisms that control the formation of primary cilia are not understood. Here we characterize a zebrafish gene, termed duboraya (dub), that is essential for ciliogenesis. Knockdown of dub in zebrafish embryos results in both defects in primary cilia formation in Kupffer's vesicle and randomization of left-right organ asymmetries. We show that, at the molecular level, the function of dub in ciliogenesis is regulated by phosphorylation, which in turn depends on Frizzled-2-mediated noncanonical Wnt signaling. We also provide evidence that, at the cellular level, dub function is essential for actin organization in the cells lining Kupffer's vesicle. Taken together, our findings identify a molecular factor that links noncanonical Wnt signaling with the control of left-right axis specification, and provide an entry point for analyzing the mechanisms that regulate primary cilia formation.

PMID: 17013396 [PubMed - indexed for MEDLINE]

18: Dev Biol. 2008 Mar 1;315(1):55-71. Epub 2007 Dec 15.Click here to read Links

Two novel type II receptors mediate BMP signalling and are required to establish left-right asymmetry in zebrafish.

Monteiro R, van Dinther M, Bakkers J, Wilkinson R, Patient R, ten Dijke P, Mummery C.

Hubrecht Institute, Netherlands Institute for Developmental Biology, Utrecht, The Netherlands.

Ligands of the transforming growth factor beta (TGFbeta) superfamily, like Nodal and bone morphogenetic protein (BMP), are pivotal to establish left-right (LR) asymmetry in vertebrates. However, the receptors mediating this process are unknown. Here we identified two new type II receptors for BMPs in zebrafish termed bmpr2a and bmpr2b that induce a classical Smad1/5/8 response to BMP binding. Morpholino-mediated knockdown of bmpr2a and bmpr2b showed that they are required for the establishment of concomitant cardiac and visceral LR asymmetry. Expression of early laterality markers in morphants indicated that bmpr2a and bmpr2b act upstream of pitx2 and the nodal-related southpaw (spaw), which are expressed asymmetrically in the lateral plate mesoderm (LPM), and subsequently regulate lefty2 and bmp4 in the left heart field. We demonstrated that bmpr2a is required for lefty1 expression in the midline at early segmentation while bmpr2a/bmpr2b heteromers mediate left-sided spaw expression in the LPM. We propose a mechanism whereby this differential interpretation of BMP signalling through bmpr2a and bmpr2b is essential for the establishment of LR asymmetry in the zebrafish embryo.

PMID: 18222420 [PubMed - indexed for MEDLINE]

19: Development. 2007 May;134(10):1921-30. Epub 2007 Apr 18.Click here to read Links

Na,K-ATPase alpha2 and Ncx4a regulate zebrafish left-right patterning.

Shu X, Huang J, Dong Y, Choi J, Langenbacher A, Chen JN.

Department of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA 90095, USA.

A conserved molecular cascade involving Nodal signaling that patterns the laterality of the lateral mesoderm in vertebrates has been extensively studied, but processes involved in the initial break of left-right (LR) symmetry are just beginning to be explored. Here we report that Na,K-ATPase alpha2 and Ncx4a function upstream of Nodal signaling to regulate LR patterning in zebrafish. Knocking down Na,K-ATPase alpha2 and Ncx4a activity in dorsal forerunner cells (DFCs), which are precursors of Kupffer's vesicle (KV), is sufficient to disrupt asymmetric gene expression in the lateral plate mesoderm and randomize the placement of internal organs, indicating that the activity of Na,K-ATPase alpha2 and Ncx4a in DFCs/KV is crucial for LR patterning. High-speed videomicroscopy and bead implantation experiments show that KV cilia are immobile and the directional fluid flow in KV is abolished in Na,K-ATPase alpha2 and Ncx4a morphants, suggesting their essential role in KV ciliary function. Furthermore, we found that intracellular Ca(2+) levels are elevated in Na,K-ATPase alpha2 and Ncx4a morphants and that the defects in ciliary motility, KV fluid flow and placement of internal organs induced by their knockdown could be suppressed by inhibiting the activity of Ca(2+)/calmodulin-dependent protein kinase II. Together, our data demonstrate that Na,K-ATPase alpha2 and Ncx4a regulate LR patterning by modulating intracellular calcium levels in KV and by influencing cilia function, revealing a previously unrecognized role for calcium signaling in LR patterning.

PMID: 17442698 [PubMed - indexed for MEDLINE]

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  • Potassium (Glu-K® , K+ 10® , K+ 8® , ...)

    Potassium is essential for the proper functioning of the heart, kidneys, muscles, nerves, and digestive system. Usually the food you eat supplies all of the potassium you need. However, certain diseases (e.g., kidney dis...

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20: Dev Dyn. 2006 Jul;235(7):1794-808.Click here to read Links

A mutation in the zebrafish Na,K-ATPase subunit atp1a1a.1 provides genetic evidence that the sodium potassium pump contributes to left-right asymmetry downstream or in parallel to nodal flow.

Ellertsdottir E, Ganz J, Dürr K, Loges N, Biemar F, Seifert F, Ettl AK, Kramer-Zucker AK, Nitschke R, Driever W.

Developmental Biology, Institute Biology 1, University of Freiburg, Freiburg, Germany.

While there is a good conceptual framework of dorsoventral and anterioposterior axes formation in most vertebrate groups, understanding of left-right axis initiation is fragmentary. Diverse mechanisms have been implied to contribute to the earliest steps of left-right asymmetry, including small molecule signals, gap junctional communication, membrane potential, and directional flow of extracellular liquid generated by monocilia in the node region. Here we demonstrate that a mutation in the zebrafish Na,K-ATPase subunit atp1a1a causes left-right defects including isomerism of internal organs at the anatomical level. The normally left-sided Nodal signal spaw as well as its inhibitor lefty are expressed bilaterally, while pitx2 may appear random or bilateral. Monocilia movement and fluid circulation in Kupffer's vesicle are normal in atp1a1a(m883) mutant embryos. Therefore, the Na,K-ATPase is required downstream or in parallel to monocilia function during initiation of left-right asymmetry in zebrafish. (c) 2006 Wiley-Liss, Inc.

PMID: 16628609 [PubMed - indexed for MEDLINE]

Patient Drug Information

  • Potassium (Glu-K® , K+ 10® , K+ 8® , ...)

    Potassium is essential for the proper functioning of the heart, kidneys, muscles, nerves, and digestive system. Usually the food you eat supplies all of the potassium you need. However, certain diseases (e.g., kidney dis...

  • Source: AHFS Consumer Medication Information
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