A01

Mechanisms of Wnt secretion in vivo

Funding period: 2017-2029

Project A01

Project Leaders

Prof. Dr. Michael Boutros

 Project Leader A01, Z01, Z03

Abstract

This project investigates Wnt secretion mechanisms from ligand producing cells. In the next funding period, we will assess context-dependent mechanisms of Wnt secretion in different tissues during development. A systematic investigation of secretion and dispersal of all Drosophila Wnts will be performed using endogenous tagging, high-resolution microscopy, and functional perturbations in different tissues. In addition, we will continue to dissect interactions of Evi/Wls with other proteins together with CRC collaborators. This will lead to a deeper understanding of how different Wnt ligands are secreted and distributed in various tissues in vivo.

Project-related Publications

Improved in vivo gene knockout with high specificity using multiplexed Cas12a sgRNAs

Port F, Buhmann MA, Zhou J, Stricker M, Vaughan-Brown A, Michalsen AC, Roßmanith E, Pöltl A, Großkurth L, Huber J, Menendez Kury LB, Weberbauer B, Hübl M, Puscher E, Heigwer F, Boutros M. Nat Commun. 2026 Jan 15;17(1):877. doi: 10.1038/s41467-026-68434-z.

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Dissecting the enhancer gene regulatory network in early Drosophila spermatogenesis

van Nierop Y Sanchez P, Sekhar PS, Yildirim K, Lange T, Kreplin LZ, Boopathy VM, Rosswag de Souza S, Dammer K, Ibberson D, Wang Q, Domsch K, Stokkermans A, Pandey S, Kaspar P, Martinez-Gallegos R, Gao X, Singh A, Engel N, Port F, Boutros M, Bageritz J, Lohmann I. Nat Commun. 2025 Jul 23;16(1):6766. doi: 10.1038/s41467-025-62046-9.

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The origin and evolution of Wnt signalling

Holzem M, Boutros M, Holstein TW. Nat Rev Genet. 2024 Feb 19. Online ahead of print. PMID: 38374446

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A temperature-tolerant CRISPR base editor mediates highly efficient and precise gene editing in Drosophila

Doll RM, Boutros M, Port F. Sci Adv. 2023 Sep;9(35):eadj1568. doi: 10.1126/sciadv.adj1568. Epub 2023 Aug 30. PMID: 37647411

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Glyoxal as alternative fixative for single cell RNA sequencing

Bageritz J, Krausse N, Yousefian S, Leible S, Valentini E, Boutros M. G3 (Bethesda). 2023 Jul 26:jkad160. doi: 10.1093/g3journal/jkad160. Online ahead of print. PMID: 37494060

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The Roles of Secreted Wnt Ligands in Cancer

Werner J, Boonekamp KE, Zhan T, Boutros M. Int J Mol Sci. 2023 Mar 10;24(6):5349. doi: 10.3390/ijms24065349. PMID: 36982422

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The role of Evi/Wntless in exporting Wnt proteins

Wolf L, Boutros M. Development. 2023 Feb 15;150(3):dev201352. doi: 10.1242/dev.201352. Epub 2023 Feb 10.
PMID: 36763105

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Superresolution microscopy localizes endogenous Dvl2 to Wnt signaling-responsive biomolecular condensates

Schubert A, Voloshanenko O, Ragaller F, Gmach P, Kranz D, Scheeder C, Miersch T, Schulz M, Trümper L, Binder C, Lampe M, Engel U, Boutros M. Proc Natl Acad Sci U S A. 2022 Jul 26;119(30):e2122476119. doi: 10.1073/pnas.2122476119. Epub 2022 Jul 22. PMID: 35867833

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EVI/WLS function is regulated by ubiquitination and linked to ER-associated degradation by ERLIN2

Wolf LM, Lambert AM, Haenlin J, Boutros M. J Cell Sci. 2021 Jul 19:jcs.257790. doi: 10.1242/jcs.257790. Online ahead of print.
PMID: 3427964

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A spatial vascular transcriptomic, proteomic, and phosphoproteomic atlas unveils an angiocrine Tie–Wnt signaling axis in the liver

Inverso D, Shi J, Lee KH, Jakab M, Ben-Moshe S, Kulkarni SR, Schneider M, Wang G, Komeili M, Vélez PA, Riedel M, Spegg C, Ruppert T, Schaeffer-Reiss C, Helm D, Singh I, Boutros M, Chintharlapalli S, Heikenwalder M, Itzkovitz S, Augustin HG. Dev Cell. 2021 Jun 7;56(11):1677-1693.e10. PMID: 34038707

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Wnt10b GSK3β dependent Wnt/STOP signaling prevents aneuploidy in human somatic cells

Lin YC, Haas A, Bufe A, Parbin S, Hennecke M, Voloshanenko O, Gross J, Boutros M, Acebron SP, Bastians H. Life Sci Alliance. 2020 Nov 30;4(1):e202000855. Print 2021 Jan.
PMID: 33257473

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Extracellular vesicles and oncogenic signaling

Schubert A, Boutros M. Mol Oncol. 2020 Nov 18. doi: 10.1002/1878-0261.12855. PMID: 33207034

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Structural Basis of Tail-Anchored Membrane Protein Biogenesis by the GET Insertase Complex

McDowell, M.A., M. Heimes, F. Fiorentino, S. Mehmood, Á. Farkas, J. Coy-Vergara, D. Wu, J.R. Bolla, V. Schmid, R. Heinze, K. Wild, D. Flemming, S. Pfeffer, B. Schwappach, C.V. Robinson, and I. Sinning. Mol Cell. 2020 Oct 1;80(1):72-86.e7. doi: 10.1016/j.molcel.2020.08.012. Epub 2020 Sep 9. PMID: 32910895

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Multiplexed conditional genome editing with Cas12a in Drosophila

Port F, Starostecka M, Boutros M. Proc Natl Acad Sci U S A. 2020 Aug 25:202004655.

PMID: 32843348

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eGFP-tagged Wnt-3a enables functional analysis of Wnt trafficking and signaling and kinetic assessment of Wnt binding to full-length Frizzled

Wesslowski J, Kozielewicz P, Wang X, Cui H, Schihada H, Kranz D, Karuna M P, Levkin P, Gross JC, Boutros M, Schulte G, Davidson G. J Biol Chem. 2020 May 7. pii: jbc.RA120.012892. PMID:32381507

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The ribosome-associated complex RAC serves in a relay that directs nascent chains to Ssb

Zhang Y, Valentín Gesé G, Conz C, Lapouge K, Kopp J, Wölfle T, Rospert S, Sinning I. Nat Commun. 2020 Mar 20;11(1):1504. doi: 10.1038/s41467-020-15313-w. PMID: 32198371

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A Large-Scale Resource for Tissue-Specific CRISPR Mutagenesis in Drosophila

Port F, Strein C, Stricker M, Rauscher B, Heigwer F, Zhou J, Beyersdörffer C, Frei J, Hess A, Kern K, Lange L, Langner N, Malamud R, Pavlović B, Rädecke K, Schmitt L, Voos L, Valentini E, Boutros M. Elife. 2020 Feb 13;9:e53865.

PMID: 32053108

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MetAP-like Ebp1 occupies the human ribosomal tunnel exit and recruits flexible rRNA expansion segments

Wild K, Aleksić M, Lapouge K, Juaire KD, Flemming D, Pfeffer S, Sinning I. Nat Commun. 2020 Feb 7;11(1):776. doi: 10.1038/s41467-020-14603-7. PMID: 32034140

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Exocyst-mediated apical Wg secretion activates signaling in the Drosophila wing epithelium

Chaudhary V, Boutros M. PLoS Genet. 2019 Sep 17;15(9):e1008351. PMID: 31527874

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Robust Wnt signaling is maintained by a Wg protein gradient and Fz2 receptor activity in the developing Drosophila wing

Chaudhary V, Hingole S, Frei J, Port F, Strutt D, Boutros M. Development. 2019 Aug 9;146(15). PMID: 31399474

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β-catenin-independent regulation of Wnt target genes by RoR2 and ATF2/ATF4 in colon cancer cells

Voloshanenko O, Schwartz U, Kranz D, Rauscher B, Linnebacher M, Augustin I, Boutros M. Sci Rep. 2018 Feb 16;8(1):3178. PMID:29453334

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ERAD-dependent control of the Wnt secretory factor Evi

Glaeser K, Urban M, Fenech E, Voloshanenko O, Kranz D, Lari F, Christianson JC, Boutros M. EMBO J. 2018 Feb 15;37(4). PMID:29378775  

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Mapping of Wnt-Frizzled interactions by multiplex CRISPR targeting of receptor gene families

Voloshanenko O, Gmach P, Winter J, Kranz D, Boutros M. FASEB J. 2017 Nov;31(11):4832-4844. doi: 10.1096/fj.201700144R. Epub 2017 Jul 21. PMID: 28733458

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Structural insights into a unique Hsp70-Hsp40 interaction in the eukaryotic ribosome-associated complex

Weyer FA, Gumiero A, Gesé GV, Lapouge K, Sinning I. Nat Struct Mol Biol. 2017 Feb;24(2):144-151. doi: 10.1038/nsmb.3349. Epub 2017 Jan 9.
PMID: 28067917

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Structural basis for tail-anchored membrane protein biogenesis by the Get3-receptor complex

Stefer S, Reitz S, Wang F, Wild K, Pang YY, Schwarz D, Bomke J, Hein C, Löhr F, Bernhard F, Denic V, Dötsch V, Sinning I. Science. 2011 Aug 5;333(6043):758-62. doi: 10.1126/science.1207125. Epub 2011 Jun 30. PMID: 21719644

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Secretion of Wnt ligands requires Evi, a conserved transmembrane protein

Bartscherer K, Pelte N, Ingelfinger D, Boutros M. Cell. 2006 May 5;125(3):523-33. doi: 10.1016/j.cell.2006.04.009. PMID: 16678096

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