RESUMEN

Although the arrangement of internal organs in most metazoans is profoundly left-right (L/R) asymmetric with a predominant handedness, rare individuals show full (mirror-symmetric) or partial (heterotaxy) reversals. While the nematode Caenorhabditis elegans is known for its highly determinate development, including stereotyped L/R organ handedness, we found that L/R asymmetry of the major organs, the gut and gonad, varies among natural isolates of the species in both males and hermaphrodites. In hermaphrodites, heterotaxy can involve one or both bilaterally asymmetric gonad arms. Male heterotaxy is probably not attributable to relaxed selection in this hermaphroditic species, as it is also seen in gonochoristic Caenorhabditis species. Heterotaxy increases in many isolates at elevated temperature, with one showing a pregastrulation temperature-sensitive period, suggesting a very early embryonic or germline effect on this much later developmental outcome. A genome-wide association study of 100 isolates showed that male heterotaxy is associated with three genomic regions. Analysis of recombinant inbred lines suggests that a small number of loci are responsible for the observed variation. These findings reveal that heterotaxy is a widely varying quantitative trait in an animal with an otherwise highly stereotyped anatomy, demonstrating unexpected plasticity in an L/R arrangement of the major organs even in a simple animal.This article is part of the themed issue 'Provocative questions in left-right asymmetry'.

Asunto(s)

Tipificación del Cuerpo , Caenorhabditis elegans/embriología , Caenorhabditis elegans/genética , Estudio de Asociación del Genoma Completo , Organogénesis , Animales , Tracto Gastrointestinal/embriología , Gónadas/embriología , Masculino

RESUMEN

Anatomical left-right (L/R) asymmetry in C. elegans is established in the four-cell embryo as a result of anteroposterior skewing of transverse mitotic spindles with a defined handedness. This event creates a chiral embryo and ultimately an adult body plan with fixed L/R positioning of internal organs and components of the nervous system. While this "dextral" configuration is invariant in hermaphrodites, it can be reversed by physical manipulation of the early embryo or by mutations that interfere with mitotic spindle orientation, which leads to viable, mirror-reversed (sinistral) animals. During normal development of the C. elegans male, the gonad develops on the right of the midline, with the gut bilaterally apposed on the left. However, we found that in males of the laboratory N2 strain and Hawaiian ("Hw") wild isolate, the gut/gonad asymmetry is frequently reversed in a temperature-dependent manner, independent of normal embryonic chirality. We also observed sporadic errors in gonad migration occurring naturally during early larval stages of these and other wild strains; however, the incidence of such errors does not correlate with the frequency of L/R gut/gonad reversals in these strains. Analysis of N2/Hw hybrids and recombinant inbred advanced intercross lines (RIAILs) indicate that the L/R organ reversals are likely to result from recessively acting variations in multiple genes. Thus, unlike the highly reproducible L/R asymmetries of most structures in hermaphrodites, the L/R asymmetry of the male C. elegans body plan is less rigidly determined and subject to natural variation that is influenced by a multiplicity of genes.

Asunto(s)

Tipificación del Cuerpo/fisiología , Caenorhabditis elegans/embriología , Gónadas/embriología , Organogénesis/fisiología , Animales , Desarrollo Embrionario/fisiología , Masculino

RESUMEN

Complex animals display bilaterally asymmetric motor behavior, or "motor handedness," often revealed by preferential use of limbs on one side. For example, use of right limbs is dominant in a strong majority of humans. While the mechanisms that establish bilateral asymmetry in motor function are unknown in humans, they appear to be distinct from those for other handedness asymmetries, including bilateral visceral organ asymmetry, brain laterality, and ocular dominance. We report here that a simple, genetically homogeneous animal comprised of only ~1000 somatic cells, the nematode C. elegans, also shows a distinct motor handedness preference: on a population basis, males show a pronounced right-hand turning bias during mating. The handedness bias persists through much of adult lifespan, suggesting that, as in more complex animals, it is an intrinsic trait of each individual, which can differ from the population mean. Our observations imply that the laterality of motor handedness preference in C. elegans is driven by epigenetic factors rather than by genetic variation. The preference for right-hand turns is also seen in animals with mirror-reversed anatomical handedness and is not attributable to stochastic asymmetric loss of male sensory rays that occurs by programmed cell death. As with C. elegans, we also observed a substantial handedness bias, though not necessarily the same preference in direction, in several gonochoristic Caenorhabditis species. These findings indicate that the independence of bilaterally asymmetric motor dominance from overall anatomical asymmetry, and a population-level tendency away from ambidexterity, occur even in simple invertebrates, suggesting that these may be common features of bilaterian metazoans.

Asunto(s)

Fenómenos Biomecánicos/fisiología , Dominancia Cerebral , Lateralidad Funcional/fisiología , Movimiento/fisiología , Conducta Sexual Animal/fisiología , Animales , Caenorhabditis elegans , Plasticidad Neuronal

RESUMEN

Dystonic movements and Parkinsonism are frequently seen in gangliosidoses and these conditions have been reported to modify dopaminergic plasticity. We investigated whether the activity of hexosaminidase, a type-two ganglioside (GM2) degrading enzyme, correlates with drug-induced extrapyramidal system (EPS) side effects in psychiatric patients. We compared hexosaminidase activity in the lymphocytes of 29 EPS-positive patients, 13 EPS-negative patients, and 30 healthy volunteers. The activities of A and B isoforms of hexosaminidase were higher in EPS-positive patients than EPS-negative patients and healthy controls. Multivariate analysis suggested an interaction with increased B isoform activity and EPS side effects in female bipolar disorder patients. Higher levels of hexosaminidase enzyme activity may explain the frequent occurrence of antipsychotic-induced extrapyramidal side effects in mood disorder patients.

Asunto(s)

Antipsicóticos/efectos adversos , Enfermedades de los Ganglios Basales/inducido químicamente , Enfermedades de los Ganglios Basales/enzimología , Hexosaminidasas/metabolismo , Linfocitos/enzimología , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Linfocitos/efectos de los fármacos , Masculino , Trastornos Mentales/tratamiento farmacológico , Persona de Mediana Edad , Análisis Multivariante , Isoformas de Proteínas/metabolismo , Factores Sexuales

RESUMEN

Little is known of the control of gene expression in the animal hemisphere of the Xenopus embryo. Here we show that expression of FoxI1e, a gene essential for normal ectoderm formation, is expressed regionally within the animal hemisphere, in a highly dynamic fashion. In situ hybridization shows that FoxI1e is expressed in a wave-like fashion that is initiated on the dorsal side of the animal hemisphere, extends across to the ventral side by the mid-gastrula stage, and is then turned off in the dorsal ectoderm, the neural plate, at the neurula stage. It is confined to the inner layers of cells in the animal cap, and is expressed in a mosaic fashion throughout. We show that this dynamic pattern of expression is controlled by both short- and long-range signals. Notch signaling controls both the mosaic, and dorsal/ventral changes in expression, and is controlled, in turn, by Vg1 signaling from the vegetal mass. FoxI1e expression is also regulated by nodal signaling downstream of VegT. Canonical Wnt signaling contributes only to late changes in the FoxI1e expression pattern. These results provide new insights into the roles of vegetally localized mRNAs in controlling zygotic genes expressed in the animal hemisphere by long-range signaling. They also provide novel insights into the role of Notch signaling at the earliest stages of vertebrate development.

Asunto(s)

Regulación del Desarrollo de la Expresión Génica , Transducción de Señal , Factores de Transcripción/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus/genética , Animales , Ectodermo/fisiología , Embrión no Mamífero , Femenino , Factores de Transcripción Forkhead , Gástrula , Hibridación in Situ , Microinyecciones , Modelos Biológicos , Placa Neural/fisiología , Oligonucleótidos Antisentido/farmacología , ARN Mensajero/administración & dosificación , Receptores Notch/metabolismo , Factores de Transcripción/genética , Xenopus/embriología , Xenopus/crecimiento & desarrollo , Proteínas de Xenopus/genética

RESUMEN

Current models of canonical Wnt signaling assume that a pathway is active if beta-catenin becomes nuclearly localized and Wnt target genes are transcribed. We show that, in Xenopus, maternal LRP6 is essential in such a pathway, playing a pivotal role in causing expression of the organizer genes siamois and Xnr3, and in establishing the dorsal axis. We provide evidence that LRP6 acts by degrading axin protein during the early cleavage stage of development. In the full-grown oocyte, before maturation, we find that axin levels are also regulated by Wnt11 and LRP6. In the oocyte, Wnt11 and/or LRP6 regulates axin to maintain beta-catenin at a low level, while in the embryo, asymmetrical Wnt11/LRP6 signaling stabilizes beta-catenin and enriches it on the dorsal side. This suggests that canonical Wnt signaling may not exist in simple off or on states, but may also include a third, steady-state, modality.

Asunto(s)

Oocitos/metabolismo , Receptores de LDL/metabolismo , Proteínas Represoras/metabolismo , Proteínas Wnt/metabolismo , Proteínas de Xenopus/metabolismo , Xenopus/embriología , Xenopus/metabolismo , beta Catenina/metabolismo , Animales , Proteína Axina , Secuencia de Bases , Tipificación del Cuerpo/genética , Tipificación del Cuerpo/fisiología , Femenino , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad , Modelos Biológicos , Oocitos/crecimiento & desarrollo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores de LDL/genética , Transducción de Señal , Xenopus/genética

RESUMEN

Xenopus Vg 1, a transforming growth factor beta (Tgfbeta) family member, was one of the first maternally localized mRNAs identified in vertebrates. Its restriction to the vegetal pole of the egg made it the ideal candidate to be the mesoderm-inducing signal released by vegetal cells, but its function in vivo has never been resolved. We show that Vg 1 is essential for Xenopus embryonic development, and is required for mesoderm induction and for the expression of several key Bmp antagonists. Although the original Vg 1 transcript does not rescue Vg 1-depleted embryos, we report that a second allele is effective. This work resolves the mystery of Vg 1 function, and shows it to be an essential maternal regulator of embryonic patterning.

Asunto(s)

Tipificación del Cuerpo/fisiología , Inducción Embrionaria/genética , Glicoproteínas/metabolismo , Mesodermo/metabolismo , Transducción de Señal/fisiología , Factor de Crecimiento Transformador beta/metabolismo , Xenopus/embriología , Xenopus/metabolismo , Secuencia de Aminoácidos , Animales , Western Blotting , Inducción Embrionaria/fisiología , Hibridación in Situ , Datos de Secuencia Molecular , Oligonucleótidos , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas de Xenopus

RESUMEN

Wnt signaling pathways play essential roles in patterning and proliferation of embryonic and adult tissues. In many organisms, this signaling pathway directs axis formation. Although the importance of intracellular components of the pathway, including beta-catenin and Tcf3, has been established, the mechanism of their activation is uncertain. In Xenopus, the initiating signal that localizes beta-catenin to dorsal nuclei has been suggested to be intracellular and Wnt independent. Here, we provide three lines of evidence that the pathway specifying the dorsal axis is activated extracellularly in Xenopus embryos. First, we identify Wnt11 as the initiating signal. Second, we show that activation requires the glycosyl transferase X.EXT1. Third, we find that the EGF-CFC protein, FRL1, is also essential and interacts with Wnt11 to activate canonical Wnt signaling.

Asunto(s)

Tipificación del Cuerpo/fisiología , Proteínas del Citoesqueleto/metabolismo , Glicoproteínas/metabolismo , Transducción de Señal/fisiología , Transactivadores/metabolismo , Xenopus/metabolismo , Animales , Tipificación del Cuerpo/genética , Proteínas del Citoesqueleto/genética , Cartilla de ADN/genética , Embrión no Mamífero/metabolismo , Femenino , Proteínas Ligadas a GPI , Regulación del Desarrollo de la Expresión Génica/genética , Regulación del Desarrollo de la Expresión Génica/fisiología , Glicoproteínas/genética , Proteínas de Homeodominio/metabolismo , Péptidos y Proteínas de Señalización Intercelular , Proteínas de la Membrana/metabolismo , N-Acetilglucosaminiltransferasas/metabolismo , Oocitos/crecimiento & desarrollo , Oocitos/metabolismo , Unión Proteica , ARN Mensajero/genética , Transducción de Señal/genética , Transactivadores/genética , Factores de Transcripción/metabolismo , Proteínas Wnt , Xenopus/embriología , Proteínas de Xenopus/metabolismo , beta Catenina

RESUMEN

XPACE4 is a member of the subtilisin/kexin family of pro-protein convertases. It cleaves many pro-proteins to release their active proteins, including members of the TGFbeta family of signaling molecules. Studies in mouse suggest it may have important roles in regulating embryonic tissue specification. Here, we examine the role of XPACE4 in Xenopus development and make three novel observations: first, XPACE4 is stored as maternal mRNA localized to the mitochondrial cloud and vegetal hemisphere of the oocyte; second, it is required for the endogenous mesoderm inducing activity of vegetal cells before gastrulation; and third, it has substrate-specific activity, cleaving Xnr1, Xnr2, Xnr3 and Vg1, but not Xnr5, Derriere or ActivinB pro-proteins. We conclude that maternal XPACE4 plays an important role in embryonic patterning by regulating the production of a subset of active mature TGFbeta proteins in specific sites.

Asunto(s)

Proproteína Convertasas/metabolismo , Serina Endopeptidasas/metabolismo , Factor de Crecimiento Transformador beta/metabolismo , Xenopus laevis/embriología , Xenopus laevis/metabolismo , Secuencia de Aminoácidos , Animales , Embrión no Mamífero/embriología , Embrión no Mamífero/metabolismo , Gástrula/metabolismo , Regulación del Desarrollo de la Expresión Génica , Humanos , Mesodermo/metabolismo , Datos de Secuencia Molecular , Madres , Oligonucleótidos Antisentido/genética , Comunicación Paracrina , Fenotipo , Proproteína Convertasas/química , Proproteína Convertasas/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Alineación de Secuencia , Serina Endopeptidasas/química , Serina Endopeptidasas/genética , Proteínas de Xenopus