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At least 19 recordsLinked to original sources
PubMed1995

Interactions of Wnt-1 and Wnt-3a are essential for neural tube patterning.

Wnt-1 and Wnt-3a have been postulated to share functional redundancy in spinal cord morphogenesis due to their homologies in protein structure and overlapping expression patterns. In this study, antisense oligonucleotides and a murine whole embryo culture system were used to examine functional interactions of Wnt-1 and Wnt-3a in late gastrulation and neurulation. Early somite mouse embryos were injected with combinations of Wnt-1 and Wnt-3a antisense oligonucleotides and then grown in vitro for up to 48 hr. Simultaneous inhibition of Wnt-1 and Wnt-3a expression resulted in pattern loss in the presumptive spinal cord, which was apparent within 4 hr following antisense treatment. The neural tube was wavy, there was a reduction in the number of nuclear layers in the walls of the neural tube, and evidence of decreased cell adhesion between neuroepithelial cells by 12 hr postinjection. In addition, notochord and primitive streak abnormalities accompanied neural tube abnormalities. The existence of regulatory interactions between Wnt-1, Wnt-3a, and engrailed genes was also examined in this study. Antisense inhibition of Wnt-1 or Wnt-3a expression resulted in reduction of engrailed protein levels in the brain, somites, and spinal cord. However, simultaneous inhibition of both Wnt genes resulted in more complete loss of engrailed protein in these regions. Herein, we present data suggesting functional redundancy of Wnt-1 and Wnt-3a in neural tube patterning and in regulation of engrailed expression.

Animals↗
PubMed1997

Frzb-1, an antagonist of Wnt-1 and Wnt-8, does not block signaling by Wnts -3A, -5A, or -11.

Frzb-1 is a secreted factor that was recently shown to inhibit signaling by Wnts 1 and 8. Frzb-1 contains an amino terminal domain that is homologous to the Drosophila polarity gene frizzled; several other secreted proteins that share this feature have now been identified. These findings raise the question of whether or not Frzb-1 is a general inhibitor of signaling by all Wnts. We show that signaling of Wnts -3A, 5A, and 11 is not blocked by Frzb-1, demonstrating that Frzb-1 can discriminate both between the principle functional Wnt classes that have been proposed and within them.

Animals↗
PubMed1993

Overlapping expression of Xwnt-3A and Xwnt-1 in neural tissue of Xenopus laevis embryos.

Xwnt-3A is a member of the Xenopus-Wnt gene family, a class of secreted, cysteine-rich proteins implicated in intercellular signaling during early development. Here we describe the full-length coding sequence of Xwnt-3A, as well as the spatial expression pattern of this Xwnt gene as determined by whole-mount in situ hybridization analysis. While Xwnt-3A shares considerable amino acid identity with both Wnt-3 (87%) and Wnt-3A (85%), its spatial expression pattern is most like that of Wnt-3A. Xwnt-3A, which is first detected at the neurula stage of development, is expressed exclusively along the dorsal midline of the developing brain and neural tube and along the dorsal surface of the otic vesicle. While the expression of Xwnt-1 extensively overlaps that of Xwnt-3A, Xwnt-1 is uniquely expressed along the midbrain/hindbrain boundary and is absent from the otic vesicle. The expression of Xwnt-3A in neural ectoderm is dependent upon neural induction as determined by experiments with recombined ectoderm and mesoderm tissue. These results suggest that Xwnt-3A may participate in patterning the central nervous system during early Xenopus development. Last, the ectopic expression of Xwnt-3A induces the formation of a secondary axis at the anterior end of the embryo.

Amino Acid Sequence↗
PubMed1995

Specification of the anteroposterior neural axis through synergistic interaction of the Wnt signaling cascade with noggin and follistatin.

Embryological data and the activities of the neural-inducing factors noggin and follistatin are consistent with the hypothesis that the nervous system is initially induced with an anterior character, with subsequent signals imparting posterior pattern. We report that Xwnt3a is a candidate for involvement in anteroposterior neural patterning, as it synergizes with the neural-inducing factors noggin and follistatin to increase the expression of posterior neural genes. Furthermore we show that beta-catenin, an intracellular protein implicated in the Wnt signal transduction cascade, mimics the activity of Xwnt3a. These data suggest that the generation of pattern within the vertebrate nervous system may rely on synergism between a Wnt signaling pathway and multiple neural-inducing factors.

Animals↗
PubMed1995

The Drosophila Wnt protein DWnt-3 is a secreted glycoprotein localized on the axon tracts of the embryonic CNS.

The Wnt gene family encodes highly conserved cysteine-rich proteins which appear to act as secreted developmental signals. Both the mouse Wnt-1 gene and the Drosophila wingless (wg) gene play important roles in central nervous system (CNS) development. wg is also required earlier, in the development of the embryonic metameric body pattern. We have begun to characterize the developmental expression and role of another member of the Drosophila Wnt gene family, DWnt-3. Using antisera raised to the DWnt-3 protein, we show that the protein is secreted in vivo. The early protein expression domains include the limb and appendage primordia. Late expression domains comprise the ventral cord and supraesophageal ganglia of the CNS. Notably, DWnt-3 protein accumulates on the commissural and longitudinal axon tracts of the CNS. Ectopic expression of DWnt-3 in transgenic embryos bearing a HS-DWnt-3 construct leads to specific disruption of the commissural axon tracts of the CNS. We also show that DWnt-3 does not functionally replace wg in an in vivo assay. Experiments with a tissue culture cell line transfected with a construct encoding the DWnt-3 gene show that DWnt-3 protein is efficiently synthesized, glycosylated, proteolytically processed, and transported to the extracellular matrix and medium. DWnt-3, therefore, encodes a secreted protein, which is likely to play a role in development of the Drosophila CNS.

Animals↗
PubMed1997

The expression of the mouse Zic1, Zic2, and Zic3 gene suggests an essential role for Zic genes in body pattern formation.

We examined the expression of Zic1, Zic2, and Zic3 genes in the mouse embryo by means of in situ hybridization. Zic genes were found as a group of genes coding for zinc finger proteins that are expressed in a restricted manner in the adult mouse cerebellum. We showed that the genes are the vertebrate homologues of Drosophila odd-paired, which may play an essential role in parasegmental subdivision and in visceral mesoderm development. The expression of the three Zic genes was first detected at gastrulation in a spatially restricted manner. At neurulation, the expression became restricted to the dorsal neural ectoderm and dorsal paraxial mesoderm. During organogenesis, the three genes were expressed in specific regions of several developing organs, including dorsal areas of the brain, spinal cord, paraxial mesenchyme, and epidermis, the marginal zone of the neural retina and distal regions of the developing limb. For all stages, significant differences in the spatial expression of Zic1, Zic2, and Zic3 were observed. Furthermore, the expression of Zic genes in Pax3, Wnt-1, and Wnt-3a mutant embryos suggested that Zic genes are not primarily regulated by the three genes which were expressed in dorsal areas similar to Zic genes. However, in open brain, a mutant with severe neural tube defects, and in the Wnt-3a mutant mice, the expression of Zic genes was changed. The changed expression pattern in Wnt-3a mutant mice suggests that Zic genes in the neural tube are regulated by the factors from notochord. Our findings suggest that Zic genes are involved in many developmental processes. Furthermore, analysis of gene expression patterns in different mouse mutants indicated that Zic genes may act upstream of many known developmental regulatory genes.

Animals↗
PubMed1997

Evidence that absence of Wnt-3a signaling promotes neuralization instead of paraxial mesoderm development in the mouse.

Wnt-3a mutant embryos show defects caudal to the forelimb level; somites are absent, the notochord is disrupted, and the central nervous system has a pronounced dysmorphology. Previous studies revealed that the primary defects of the mutant embryos are likely to be in the process of paraxial mesoderm formation. In this study, we analyzed the phenotype of Wnt-3a mutant embryos at early somite stages (8.0 days post coitum), when somite formation is initiated. In Wnt-3a mutants, cells which have ingressed through the primitive streak do not migrate laterally but remain under the streak and form an ectopic tubular structure. Several neural-specific molecular markers, but no paraxial mesoderm markers, are expressed in this structure, suggesting that the ectopic tube is an additional neural tube. In normal embryos, Wnt-3a is expressed in the primitive ectoderm, including the cells which are fated to give rise to the paraxial mesoderm and neurectoderm, but expression is absent in migrating mesoderm cells. These results suggest that Wnt-3a signaling may play a role in regulating paraxial mesodermal fates, at the expense of neurectodermal fates, within the primitive ectoderm of the gastrulating mouse embryo.

Animals↗
PubMed1997

A role for WNT proteins in induction of dermomyotome.

Dorsoventral patterning of somites into sclerotome and dermomyotome involves antagonistic actions of ventralizing and dorsalizing signals originating from tissues surrounding the somites. The notochord and the floor plate of the neural tube provide a ventralizing signal(s) directing sclerotome development, whereas the surface ectoderm and dorsal neural tube provide a dorsalizing signal(s) directing dermomyotome development. Evidence has been provided that Sonic Hedgehog mediates the ventralizing effects of notochord and floor plate, but the dorsalizing signal(s) that patterns the dermomyotome has not been identified. The documented expression of Wnt1 and Wnt3a in the dorsal neural tube and of Wnt4 and Wnt6 in the surface ectoderm at the time of dermomyotome specification prompted us to investigate the involvement of WNT proteins in patterning the dermomyotome. Here we show that tissue culture cells expressing these WNT family members can maintain and induce dermomyotome marker expression in presomitic mesoderm explants, supporting the hypothesis that WNT proteins mediate the dorsalizing effects of the surface ectoderm and dorsal neural tube on somites.

Animals↗
PubMed2001

Wnt and BMP signaling govern lineage segregation of melanocytes in the avian embryo.

Recent studies show that specification of some neural crest lineages occurs prior to or at the time of migration from the neural tube. We investigated what signaling events establish the melanocyte lineage, which has been shown to migrate from the trunk neural tube after the neuronal and glial lineages. Using in situ hybridization, we find that, although Wnts are expressed in the dorsal neural tube throughout the time when neural crest cells are migrating, the Wnt inhibitor cfrzb-1 is expressed in the neuronal and glial precursors and not in melanoblasts. This expression pattern suggests that Wnt signaling may be involved in specifying the melanocyte lineage. We further report that Wnt-3a-conditioned medium dramatically increases the number of pigment cells in quail neural crest cultures while decreasing the number of neurons and glial cells, without affecting proliferation. Conversely, BMP-4 is expressed in the dorsal neural tube throughout the time when neural crest cells are migrating, but is decreased coincident with the timing of melanoblast migration. This expression pattern suggests that BMP signaling may be involved in neural and glial cell differentiation or repression of melanogenesis. Purified BMP-4 reduces the number of pigment cells in culture while increasing the number of neurons and glial cells, also without affecting proliferation. Our data suggest that Wnt signaling specifies melanocytes at the expense of the neuronal and glial lineages, and further, that Wnt and BMP signaling have antagonistic functions in the specification of the trunk neural crest.

Animals↗
PubMed2001

Multiple pathways governing Cdx1 expression during murine development.

Cdx1 encodes a mammalian homeobox gene involved in vertebral patterning. Retinoic acid (RA) is likewise implicated in vertebral patterning. We have previously shown that Cdx1 is a direct retinoid target gene, suggesting that Cdx1 may convey some of the effects of retinoid signaling. However, RA appears to be essential for only early stages of Cdx1 expression, and therefore other factors must be involved in maintaining later stages of expression. Based on function and pattern of expression, Wnt family members, in particular Wnt3a, are candidates for regulation of expression of Cdx1. Consistent with this, we confirm prior results which demonstrated that Cdx1 can be directly regulated by Wnt signaling, and identify functional LEF/TCF response motifs essential for this response. We also find that Cdx1 expression is markedly attenuated in a stage- and tissue-specific fashion in the Wnt3a hypomorph vestigial tail, and present data demonstrating that Wnt3a and RA synergize strongly to activate Cdx1. Finally, we show that Cdx1 positively regulates its own expression. These data prompt a model whereby retinoid and Wnt signaling function directly and synergistically to initiate Cdx1 expression in the caudal embryo. Expression is then maintained, at least in part, by an autoregulatory mechanism at later stages.

Animals↗
PubMed1995

Biochemical analysis of murine Wnt proteins reveals both shared and distinct properties.

The murine Wnt family of proteins consists of at least 12 members that possess significant amino acid homology. Current evidence suggests that these proteins are secreted cell-signaling molecules which are likely to have multiple roles during both embryonic development and oncogenesis. Although the biochemical properties of Wnt-1 have been thoroughly examined, less is known about the characteristics of other Wnt family members. We have compared the properties of six murine Wnt proteins (Wnt-1, Wnt-3a, Wnt-5a, Wnt-5b, Wnt-6, and Wnt-7b) transiently expressed in COS cells. All members enter the endoplasmic reticulum (ER) and are glycosylated. However, all six Wnt proteins are primarily retained in the ER in association with BiP, a resident ER protein that binds to improperly folded proteins and prevents their secretion and/or promotes proper folding. Although all Wnt family members examined are similarly processed, one notable difference was identified. Whereas addition of suramin to COS cell cultures significantly increases the levels of all six Wnts in the medium, the addition of heparin only influences the levels of Wnt-1, Wnt-6, and Wnt-7b.

Amino Acid Sequence↗
PubMed1992

Regional expression of the Wnt-3 gene in the developing mouse forebrain in relationship to diencephalic neuromeres.

During early vertebrate development, a series of neuromeres divides the central nervous system from the forebrain to the spinal cord. Here we examine in more detail the expression of Wnt-3, a member of the Wnt gene family of secreted proteins, in the developing diencephalon, in comparison to the expression of the homeobox gene Dlx-1. In 9.5-day mouse embryos, Wnt-3 is expressed in a restricted area of the diencephalon before any morphological signs of subdivisions appear. Around embryonic day 11.5, Wnt-3 expression becomes restricted to one of the neuromeres of the diencephalon, the dorsal thalamus. Dlx-1 is expressed in a non-overlapping area immediately anterior to and abutting the Wnt-3 expressing domain, corresponding to the ventral thalamus. In addition, Wnt-3 is expressed in the midbrain-hindbrain region. In the adult mouse, Wnt-3 and Dlx-1 are expressed in subsets of neural cells derived from the original areas of expression in the diencephalon. Taken together, our results suggest that Wnt-3 and Dlx-1 provide positional information for the regional specification of neuromeres in the forebrain. The continued expression of these genes in the adult mouse brain suggests a distinct role in the mature CNS.

Aging↗
PubMed1995

Wnt expression patterns in chick embryo nervous system.

Several lines of evidence suggest that Wnt genes play a critical role in regulating development of the vertebrate embryo. To address the role that this family may play in the development of the chicken central nervous system (CNS), we have used a PCR based strategy to clone partial sequences for Wnt genes. At least six different Wnt genes are expressed in the developing CNS of the chick embryo. The domains of expression overlap either partially or completely, and are expressed in spatial domains that prefigure morphological subunits of the embryonic neural tube. Wnt-1 and Wnt-4 are first expressed in the open neural plate in the region of the presumptive mesencephalon. Wnt-3a expression is first observed in the rhombencephalic regions of the open neural plate. After neural tube closure, when the embryonic subdivisions of the neural tube became apparent, Wnt-1, Wnt-3a and Wnt-4 are all broadly expressed in partially overlapping domains in the mesencephalon and caudal diencephalon, as well as in the rhombencephalon and spinal cord. The mesencephalic expression patterns are subsequently modified such that Wnt-1 and Wnt-4 are expressed in a characteristic ring just rostral to the isthmus, at the mesencephalic/metencephalic junction; and Wnt-1 and Wnt-3a expression become restricted to the dorsal midline. Wnt-1, Wnt-3a, Wnt-4, Wnt-5a and Wnt-8b are expressed in one or two caudal subdivisions of the developing diencephalon, the synencephalon and posterior parencephalon, but do not extend ventral to the zona limitans interparencephalica. In contrast, Wnt-7b is expressed in the anterior parencephalon. Both Wnt-7b and Wnt-8b are expressed in telencephalic portions of the secondary prosencephalon. The timing and spatial distribution of Wnt-gene expression in the chick embryo further support the general hypothesis that Wnt genes play key roles in patterning the developing vertebrate nervous system.

Amino Acid Sequence↗
PubMed2001

LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.

In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Dorsal dermis development depends on a signal from the dorsal neural tube, which can be substituted by Wnt-1.

To investigate the origin and nature of the signals responsible for specification of the dermatomal lineage, excised axial organs in 2-day-old chick embryos were replaced by grafts of the dorsal neural tube, or the ventral neural tube plus the notochord, or aggregates of cells engineered to produce Sonic hedgehog (Shh), Noggin, BMP-2, Wnt-1, or Wnt-3a. By E10, grafts of the ventral neural tube plus notochord or of cells producing Shh led to differentiation of cartilage and muscles, and an impaired dermis derived from already segmented somites. In contrast, grafts of the dorsal neural tube, or of cells producing Wnt-1, triggered the formation of a feather-inducing dermis. These results show that the dermatome inducer is produced by the dorsal neural tube. The signal can be Wnt-1 itself, or can be mediated, or at least mimicked by Wnt-1.

Animals↗
PubMed2001

Wnt-3a is required for somite specification along the anteroposterior axis of the mouse embryo and for regulation of cdx-1 expression.

In vertebrates, each vertebra along the anteroposterior axis has a characteristic structure. It has recently been shown that several transcription factors and cell signaling molecules expressed in the primitive streak ectoderm and/or the tailbud play essential roles in establishing the correct anteroposterior specification of vertebrae during mouse development. Here, we report that Wnt-3a mutants exhibit homeotic transformations in the vertebrae along their entire body axis. In addition, reduced expression of cdx-1, the mutation of which results in an anterior transformation, as occurs in Wnt-3a mutants, was observed in the primitive streak and tail bud region of Wnt-3a mutant embryos. These results indicate that Wnt-3a is necessary for correct anteroposterior patterning of vertebra, and that cdx-1 may be one of the mediator genes of Wnt-3a signaling in this process.

Alleles↗