A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling.

Zebrafish Prickle, a Modulator of Noncanonical Wnt/Fz Signaling, Regulates Gastrulation Movements

Polarized cell movements shape the major features of the vertebrate body plan during development. The head-to-tail body axis of vertebrates is elongated in embryonic stages by "convergent extension" tissue movements. During these movements cells intercalate between one another transverse to the elongating body axis to form a narrower, longer array. Recent discoveries show that these polarized cell movements are controlled by homologs of genes that control the polarity of epithelial cells in the developing wing and eye of the fruit fly, Drosophila.

https://science.sciencemag.org/content/sci/298/5600/1950.full.pdf

Shaping the Vertebrate Body Plan by Polarized Embryonic Cell Movements

In mammals, an example of planar cell polarity (PCP) is the uniform orientation of the hair cell stereociliary bundles within the cochlea. The PCP pathway of Drosophila refers to a conserved signalling pathway that regulates the coordinated orientation of cells or structures within the plane of an epithelium. Here we show that a mutation in Vangl2, a mammalian homologue of the Drosophila PCP gene Strabismus/Van Gogh, results in significant disruptions in the polarization of stereociliary bundles in mouse cochlea as a result of defects in the direction of movement and/or anchoring of the kinocilium within each hair cell. Similar, but less severe, defects are observed in animals containing a mutation in the LAP protein family gene Scrb1 (homologous with Drosophila scribble). Polarization defects in animals heterozygous for Vangl2 and Scrb1 are comparable with Vangl2 homozygotes, demonstrating genetic interactions between these genes in the regulation of PCP in mammals. These results demonstrate a role for the PCP pathway in planar polarization in mammals, and identify Scrb1 as a PCP gene.

Identification of Vangl2 and Scrb1 as planar polarity genes in mammals

More than 80 mutant mouse genes disrupt neurulation and allow an in-depth analysis of the underlying developmental mechanisms. Although many of the genetic mutants have been studied in only rudimentary detail, several molecular pathways can already be identified as crucial for normal neurulation. These include the planar cell-polarity pathway, which is required for the initiation of neural tube closure, and the sonic hedgehog signalling pathway that regulates neural plate bending. Mutant mice also offer an opportunity to unravel the mechanisms by which folic acid prevents neural tube defects, and to develop new therapies for folate-resistant defects.

The genetic basis of mammalian neurulation

The signaling mechanisms that specify, guide and coordinate cell behavior during embryonic morphogenesis are poorly understood. We report that a Xenopus homolog of the Drosophila planar cell polarity gene strabismus (stbm) participates in the regulation of convergent extension, a critical morphogenetic process required for the elongation of dorsal structures in vertebrate embryos. Overexpression of Xstbm, which is expressed broadly in early development and subsequently in the nervous system, causes severely shortened trunk structures; a similar phenotype results from inhibiting Xstbm translation using a morpholino antisense oligo. Experiments with Keller explants further demonstrate that Xstbm can regulate convergent extension in both dorsal mesoderm and neural tissue. The specification of dorsal tissues is not affected. The Xstbm phenotype resembles those obtained with several other molecules with roles in planar polarity signaling, including Dishevelled and Frizzled-7 and -8. Unlike these proteins, however, Stbm has little effect on conventional Wnt/β-catenin signaling in either frog or fly assays. Thus our results strongly support the emerging hypothesis that a vertebrate analog of the planar polarity pathway governs convergent extension movements.

/pdf/the-planar-polarity-gene-strabismus-regulates-convergent-3vdzvmh1pj.pdf

The planar polarity gene strabismus regulates convergent extension movements in Xenopus

Frizzled (Fz) signaling regulates the establishment of planar cell polarity (PCP). The PCP genes prickle (pk) and strabismus (stbm) are thought to antagonize Fz signaling. We show that they act in the same cell, R4, adjacent to that in which the Fz/PCP pathway is required in the Drosophila eye. We demonstrate that Stbm and Pk interact physically and that Stbm recruits Pk to the cell membrane. Through this interaction, Pk affects Stbm membrane localization and can cause clustering of Stbm. Pk is also known to interact with Dsh and is thought to antagonize Dsh by affecting its membrane localization. Thus our data suggest that the Stbm/Pk complex modulates Fz/Dsh activity, resulting in a symmetry-breaking step during polarity signaling.

/pdf/prickle-and-strabismus-form-a-functional-complex-to-generate-c4s1pzobw0.pdf

Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling

Following fertilization, the zygotic genome in many organisms is quiescent

until the midblastula transition (MBT), when large-scale transcription begins.

In Xenopus embryos, for example, transcription is believed to be

repressed until the twelfth cell division. Thus, although dorsal-ventral

patterning begins during the first cell cycle, little attention has been given

to transcriptional regulation in pre-MBT development. We present evidence that

regulated transcription begins during early cleavage stages and that the
β
-catenin—Tcf complex is required for the transcription of the

Xenopus nodal genes Xnr5 and Xnr6 as early as the

256-cell stage. Moreover, inhibition of β-catenin/Tcf function can block

dorsal development, but only if the inhibition begins early and is maintained

throughout pre-MBT stages. Dorsal development can be rescued in ventralized

embryos if Tcf-dependent transcription is activated prior to MBT, but

activation of Tcf after MBT cannot rescue ventralized embryos, suggesting that
β
-catenin/Tcf-dependent transcription is required prior to MBT for

dorsal-ventral patterning in Xenopus.

Paul A. Wilson

Papers

The planar polarity gene strabismus regulates convergent extension movements in Xenopus

Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling

β-Catenin/Tcf-regulated transcription prior to the midblastula transition

Axis induction by wnt signaling: Target promoter responsiveness regulates competence.