{"@context":"http://iiif.io/api/presentation/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/manifest.json","@type":"sc:Manifest","label":"The Role of MESD in WNT Signaling and Lipoprotein Metabolism","metadata":[{"label":"dc.description.sponsorship","value":"This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree."},{"label":"dc.format","value":"Monograph"},{"label":"dc.format.medium","value":"Electronic Resource"},{"label":"dc.identifier.uri","value":"http://hdl.handle.net/1951/55528"},{"label":"dc.language.iso","value":"en_US"},{"label":"dc.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.abstract","value":"Deletion of the mesoderm development (Mesd) gene region blocks gastrulation and mesoderm differentiation in mice. In cell culture, MESD is required for the localization of WNT co-receptors LRP5/6 to the cell membrane. For this reason, loss of LRP5/6 from the cell surface in Mesd mutants likely prevents WNT signaling and is responsible for the polarity defects observed in Mesd-deficient embryos. In this study, we generated a targeted Mesd knockout and verified that loss of Mesd blocks WNT signaling in vivo and mesoderm differentiation. We also identified essential domains in the MESD protein, and demonstrated that MESD function in vitro was essential for maturation of the LRP5/6Β-propeller/EGFs. Based on these results, we hypothesized that MESD function may extend more broadly to the LRP family of receptors.      The majority of LRPs contain at least one extracellularΒ-propeller and C-terminal EGF, but several, including LRP1 and LRP2, contain multipleΒ-propeller/EGF domains in tandem and therefore likely require MESD for function. LRP1 and LRP2 are classified as scavenger receptors, but also play important signaling roles in preventing atherosclerosis and holoprosencephaly, respectively. We observed that LRP1 and LRP2 transcripts are present in mid-gastrulation embryos, and demonstrated that LRP2 is strongly expressed in the apical membrane of the visceral endoderm (VE). Consistent with our prediction, we show that MESD function in vivo extends to MEGALIN (LRP2) and is essential for the apical localization of LRP2 in the VE and the normal function of this absorptive epithelia.      The phenotype of Mesd mutants is more severe than either Lrp5/6, Lrp1, or Lrp2 mutants. Although development of both Mesd and Lrp5/6 mutants arrests before gastrulation (E6.5), the size of the Mesd embryo is considerably smaller than Lrp5/6 mutants by E7.5. In contrast, Lrp1 mutants can be recovered through E13.5, and Lrp2 can be recovered at birth. Combined, phenotypic differences as well as the biochemical results described above provides evidence that MESD likely functions as a general LRP chaperone, and that the Mesd phenotype results from a combination of endocytic and signaling defects resulting from mis-folding of multiple LRP receptors."},{"label":"dcterms.available","value":"2015-04-24T14:52:43Z"},{"label":"dcterms.contributor","value":"John Peter Gergen"},{"label":"dcterms.creator","value":"Lighthouse, Janet"},{"label":"dcterms.dateAccepted","value":"2015-04-24T14:52:43Z"},{"label":"dcterms.dateSubmitted","value":"2015-04-24T14:52:43Z"},{"label":"dcterms.description","value":"Department of Molecular and Cellular Biology"},{"label":"dcterms.format","value":"Monograph"},{"label":"dcterms.identifier","value":"http://hdl.handle.net/1951/55528"},{"label":"dcterms.issued","value":"2010-12-01"},{"label":"dcterms.language","value":"en_US"},{"label":"dcterms.provenance","value":"Made available in DSpace on 2012-05-15T18:04:55Z (GMT). No. of bitstreams: 1\nLighthouse_grad.sunysb_0771E_10300.pdf: 2625721 bytes, checksum: 2d853491c1f142d62008a45401935d94 (MD5)\n  Previous issue date:    1"},{"label":"dcterms.publisher","value":"The Graduate School, Stony Brook University: Stony Brook, NY."},{"label":"dcterms.subject","value":"lipoprotein, LRP, MESD, mouse, WNT"},{"label":"dcterms.title","value":"The Role of MESD in WNT Signaling and Lipoprotein Metabolism"},{"label":"dcterms.type","value":"Dissertation"},{"label":"dc.type","value":"Dissertation"}],"description":"This manifest was generated dynamically","viewingDirection":"left-to-right","sequences":[{"@type":"sc:Sequence","canvases":[{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json","@type":"sc:Canvas","label":"Page 1","height":1650,"width":1275,"images":[{"@type":"oa:Annotation","motivation":"sc:painting","resource":{"@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/13%2F49%2F30%2F134930182814791048251535627969705064367/full/full/0/default.jpg","@type":"dctypes:Image","format":"image/jpeg","height":1650,"width":1275,"service":{"@context":"http://iiif.io/api/image/2/context.json","@id":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/13%2F49%2F30%2F134930182814791048251535627969705064367","profile":"http://iiif.io/api/image/2/level2.json"}},"on":"https://repo.library.stonybrook.edu/cantaloupe/iiif/2/canvas/page-1.json"}]}]}]}