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      Snx3 is important for mammalian neural tube closure via its role in canonical and non-canonical WNT signaling

      1 , 2 , 3 , 4 , 4 , 2
      Development
      The Company of Biologists

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          ABSTRACT

          Disruptions in neural tube (NT) closure result in neural tube defects (NTDs). To understand the molecular processes required for mammalian NT closure, we investigated the role of Snx3, a sorting nexin gene. Snx3 −/− mutant mouse embryos display a fully-penetrant cranial NTD. In vivo, we observed decreased canonical WNT target gene expression in the cranial neural epithelium of the Snx3 −/− embryos and a defect in convergent extension of the neural epithelium. Snx3 −/− cells show decreased WNT secretion, and live cell imaging reveals aberrant recycling of the WNT ligand-binding protein WLS and mis-trafficking to the lysosome for degradation. The importance of SNX3 in WNT signaling regulation is demonstrated by rescue of NT closure in Snx3 −/− embryos with a WNT agonist. The potential for SNX3 to function in human neurulation is revealed by a point mutation identified in an NTD-affected individual that results in functionally impaired SNX3 that does not colocalize with WLS and the degradation of WLS in the lysosome. These data indicate that Snx3 is crucial for NT closure via its role in recycling WLS in order to control levels of WNT signaling.

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          Sonic hedgehog and the molecular regulation of mouse neural tube closure.

          Neural tube closure is a fundamental embryonic event whose molecular regulation is poorly understood. As mouse neurulation progresses along the spinal axis, there is a shift from midline neural plate bending to dorsolateral bending. Here, we show that midline bending is not essential for spinal closure since, in its absence, the neural tube can close by a 'default' mechanism involving dorsolateral bending, even at upper spinal levels. Midline and dorsolateral bending are regulated by mutually antagonistic signals from the notochord and surface ectoderm. Notochordal signaling induces midline bending and simultaneously inhibits dorsolateral bending. Sonic hedgehog is both necessary and sufficient to inhibit dorsolateral bending, but is neither necessary nor sufficient to induce midline bending, which seems likely to be regulated by another notochordal factor. Attachment of surface ectoderm cells to the neural plate is required for dorsolateral bending, which ensures neural tube closure in the absence of sonic hedgehog signaling.
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            BMP signaling is essential for development of skeletogenic and neurogenic cranial neural crest.

            BMP signaling is essential for a wide variety of developmental processes. To evaluate the role of Bmp2/4 in cranial neural crest (CNC) formation or differentiation after its migration into the branchial arches, we used Xnoggin to block their activities in specific areas of the CNC in transgenic mice. This resulted in depletion of CNC cells from the targeted areas. As a consequence, the branchial arches normally populated by the affected neural crest cells were hypomorphic and their skeletal and neural derivatives failed to develop. In further analyses, we have identified Bmp2 as the factor required for production of migratory cranial neural crest. Its spatial and temporal expression patterns mirror CNC emergence and Bmp2 mutant embryos lack both branchial arches and detectable migratory CNC cells. Our results provide functional evidence for an essential role of BMP signaling in CNC development.
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              Phenotypic and molecular analysis of a transgenic insertional allele of the mouse Fused locus.

              Spontaneous mutations at the mouse Fused (Fu) locus cause dominant skeletal and neurological defects and recessive lethal embryonic defects including neuroectodermal abnormalities and axial duplications. Here, we describe a new allele at the Fu locus caused by a transgenic insertional mutation, H epsilon 46. Embryos homozygous for the H epsilon 46 insertion die at day 9-10 post coitum and display phenotypic defects similar to those associated with Fu alleles. The H epsilon 46 locus was cloned and shown to contain a 20-kb deletion at the site of transgene insertion with no other detectable rearrangements. Genomic probes from the H epsilon 46 locus were mapped to a genetic locus closely linked to Fu on chromosome 17 and were hybridized to a YAC contig covering the FuKi critical region. Compound heterozygotes between H epsilon 46 and FuKi were inviable and displayed abnormalities at the same stage of embryogenesis as do homozygotes for either of the two mutations, demonstrating that these two recessive lethal mutations belong to the same complementation group. A genomic probe from the wild-type H epsilon 46 locus detected a transcript that is disrupted by the transgenic insertion, representing a candidate for the wild-type allele of Fused.
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                Author and article information

                Contributors
                (View ORCID Profile)
                (View ORCID Profile)
                Journal
                Development
                Development
                The Company of Biologists
                0950-1991
                1477-9129
                November 19 2020
                November 15 2020
                November 19 2020
                November 15 2020
                : 147
                : 22
                : dev192518
                Affiliations
                [1 ]Cell Biology, Stem Cells, and Developmental Biology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
                [2 ]Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80309, USA
                [3 ]The Jackson Laboratory, Bar Harbor, ME 04609, USA
                [4 ]Department of Pediatrics, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
                Article
                10.1242/dev.192518
                33214242
                efefa8b3-b1f1-4bec-a87a-27e5c014f5ee
                © 2020

                http://www.biologists.com/user-licence-1-1/

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