H,K-ATPase protein localization and Kir4.1 function reveal concordance of three axes during early determination of left–right asymmetry

Aw, Sherry; Adams, Dany S.; Qiu, Dayong; Levin, Michael

doi:10.1016/j.mod.2007.10.011

Cited by 85 publications

(119 citation statements)

References 152 publications

(179 reference statements)

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“…A second cilia-independent model proposes that asymmetry is generated from a chirally oriented cytoskeleton (Danilchik et al, 2006; Aw et al, 2008) and the asymmetric intracellular localization of motor proteins [i.e. kinesin and LRD (Qiu et al, 2005)] and cell polarity proteins (Bunney et al, 2003a).…”

Section: Introductionmentioning

confidence: 99%

“…kinesin and LRD (Qiu et al, 2005)] and cell polarity proteins (Bunney et al, 2003a). Because of their LR-biased localizations, these motor and polarity proteins distribute ion transporters in a biased manner between the early blastomeres (Levin, 2006); the asymmetrically distributed cargo includes two proton pumps (Levin et al, 2002; Adams et al, 2006) and two potassium channels (Aw et al, 2008; Morokuma et al, 2008b). Coupled with a network of open gap junctions, the pH gradients and differences in membrane voltage that result from the biased localization of these ion transporters allow charged molecules such as serotonin to be distributed to the right- and ventral-most blastomere (Fukumoto et al, 2005a; Fukumoto et al, 2005b).…”

Section: Introductionmentioning

confidence: 99%

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Laterality defects are influenced by timing of treatments and animal model

Vandenberg

2012

Differentiation

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The timing of when the embryonic left-right (LR) axis is first established and the mechanisms driving this process are subjects of strong debate. While groups have focused on the role of cilia in establishing the LR axis during gastrula and neurula stages, many animals appear to orient the LR axis prior to the appearance of, or without the benefit of, motile cilia. Because of the large amount of data available in the published literature and the similarities in the type of data collected across labs, I have examined relationships between the studies that do and do not implicate cilia, the choice of animal model, the kinds of LR patterning defects observed, and the penetrance of LR phenotypes. I found that treatments affecting cilia structure and motility had a higher penetrance for both altered gene expression and improper organ placement compared to treatments that affect processes in early cleavage stage embryos. I also found differences in penetrance that could be attributed to the animal models used; the mouse is highly prone to LR randomization. Additionally, the data were examined to address whether gene expression can be used to predict randomized organ placement. Using regression analysis, gene expression was found to be predictive of organ placement in frogs, but much less so in the other animals examined. Together, these results challenge previous ideas about the conservation of LR mechanisms, with the mouse model being significantly different from fish, frogs and chick in almost every aspect examined. Additionally, this analysis indicates that there may be missing pieces in the molecular pathways that dictate how genetic information becomes organ positional information in vertebrates; these gaps will be important for future studies to identify, as LR asymmetry is not only a fundamentally fascinating aspect of development but also of considerable biomedical importance.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Laterality defects are influenced by timing of treatments and animal model

Vandenberg

2012

Differentiation

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“…A significant percentage (64.7% for tub4a and 32.5% for tubgcp2) of mutant-injected embryos displayed incorrect Xnr-1 expression (Fig. 2), showing that these tubulin mutations affect LR asymmetry upstream of Nodal expression.One model is that mutant tubulins perturb the normal rightward bias in the intracellular transport provided by the cytoskeleton in cleavage-stage frog embryos (19,24). These oriented cytoskeletal tracks allow cytoplasmic motors, such as kinesins and dyneins, to localize specific protein cargo to the left or right sides.…”

mentioning

confidence: 99%

Early, nonciliary role for microtubule proteins in left–right patterning is conserved across kingdoms

Lobikin

Wang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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104

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Many types of embryos' bodyplans exhibit consistently oriented laterality of the heart, viscera, and brain. Errors of left-right patterning present an important class of human birth defects, and considerable controversy exists about the nature and evolutionary conservation of the molecular mechanisms that allow embryos to reliably orient the left-right axis. Here we show that the same mutations in the cytoskeletal protein tubulin that alter asymmetry in plants also affect very early steps of left-right patterning in nematode and frog embryos, as well as chirality of human cells in culture. In the frog embryo, tubulin α and tubulin γ-associated proteins are required for the differential distribution of maternal proteins to the left or right blastomere at the first cell division. Our data reveal a remarkable molecular conservation of mechanisms initiating left-right asymmetry. The origin of laterality is cytoplasmic, ancient, and highly conserved across kingdoms, a fundamental feature of the cytoskeleton that underlies chirality in cells and multicellular organisms.C. elegans | Xenopus | symmetry breaking C onsistent laterality is a fascinating aspect of embryonic development and has considerable implications for the physiology and behavior of the organism. Although vertebrates are generally bilaterally symmetric externally, most internal organs, such as the heart, viscera, and brain display asymmetric structure and/or unilateral positioning with respect to the left-right (LR) axis. A common defect in LR patterning is the loss of concordance among the sidedness of individual organs known as heterotaxia. In human beings, abnormalities in the proper development of laterality occur in more than 1 in 8,000 live births and often have significant medical consequences (1). Organ asymmetry is highly conserved among species; however, considerable controversy exists about the early steps of LR patterning among phyla (2-4) and the physical mechanisms that can break symmetry (5).One model predicts that cilia-driven extracellular fluid flow during gastrulation is the origin of LR asymmetry (6). Because numerous species initiate asymmetry before (or without) the presence of cilia (7,8), this model implies that asymmetry generation must be poorly conserved, with numerous distinct mechanisms used throughout phyla. However, "ciliary" proteins, such as left-right dynein, known to be important for LR patterning, also have intracellular roles compatible with cilia-independent functions in laterality (9-12). In contrast to the nodal flow model, we have suggested that asymmetry is instead an ancient, well-conserved property of individual cells arising from the chirality of cytoskeletal structures that is subsequently amplified by physiological mechanisms (4,12,13). Thus, we sought the most evolutionarily distant model systems, and ones that are known not to rely on cilia for LR patterning, to test the hypothesis of fundamental molecular conservation of asymmetry mechanisms.Recent findings in Arabidopsis thaliana have shown that mutatio...

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“…To contribute to basic developmental biology and regenerative medicine (seeking novel ways to rationally modulate the position, identity, and number of embryonic stem cells), we performed molecular and pharmacological screens (18,19) for ion flows that regulate stem cell behavior during pattern formation. We uncovered a role for a channel in neural crest regulation: KCNQ1/ KCNE1.…”

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confidence: 99%

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

Morokuma¹,

Blackiston²,

Adams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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102

124

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Ion transporters, and the resulting voltage gradients and electric fields, have been implicated in embryonic development and regeneration. These biophysical signals are key physiological aspects of the microenvironment that epigenetically regulate stem and tumor cell behavior. Here, we identify a previously unrecognized function for KCNQ1, a potassium channel known to be involved in human Romano-Ward and Jervell-Lange-Nielsen syndromes when mutated. Misexpression of its modulatory wild-type ␤-subunit XKCNE1 in the Xenopus embryo resulted in a striking alteration of the behavior of one type of embryonic stem cell: the pigment cell lineage of the neural crest. Depolarization of embryonic cells by misexpression of KCNE1 non-cell-autonomously induced melanocytes to overproliferate, spread out, and become highly invasive of blood vessels, liver, gut, and neural tube, leading to a deeply hyperpigmented phenotype. This effect is mediated by the up-regulation of Sox10 and Slug genes, thus linking alterations in ion channel function to the control of migration, shape, and mitosis rates during embryonic morphogenesis. Taken together, these data identify a role for the KCNQ1 channel in regulating key cell behaviors and reveal the molecular identity of a biophysical switch, by means of which neoplastic-like properties can be conferred upon a specific embryonic stem cell subpopulation.cancer ͉ ion channel ͉ melanocyte ͉ neural crest ͉ KCNQ

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H,K-ATPase protein localization and Kir4.1 function reveal concordance of three axes during early determination of left–right asymmetry

Cited by 85 publications

References 152 publications

Laterality defects are influenced by timing of treatments and animal model

Laterality defects are influenced by timing of treatments and animal model

Early, nonciliary role for microtubule proteins in left–right patterning is conserved across kingdoms

Modulation of potassium channel function confers a hyperproliferative invasive phenotype on embryonic stem cells

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