MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus.


Type
Article
Change log
Abstract

The choroid plexus (ChP) produces cerebrospinal fluid and forms an essential brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is crucial for determining fourth ventricle (4V) ChP morphogenesis and size in mouse. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at embryonic day 10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical WNT signaling via ROR1 and ROR2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.

Description
Keywords
Choroid plexus, Epithelium, Meis1, Meis2, Morphogenesis, WNT5a, Animals, Brain, CRISPR-Cas Systems, Cell Line, Choroid Plexus, Epithelial Cells, Epithelium, Female, Fourth Ventricle, HEK293 Cells, Humans, Mice, Mice, Knockout, Myeloid Ecotropic Viral Integration Site 1 Protein, Promoter Regions, Genetic, Receptor Tyrosine Kinase-like Orphan Receptors, Signal Transduction, Wnt-5a Protein
Journal Title
Development
Conference Name
Journal ISSN
0950-1991
1477-9129
Volume Title
148
Publisher
The Company of Biologists
Rights
All rights reserved
Sponsorship
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
(LM2018129 funded by MEYS CR), Czech Centre for Phenogenomics (LM2015040), Higher quality and capacity of transgenic model breeding (by MEYS and ERDF, OP RDI CZ.1.05/2.1.00/19.0395), Czech Centre for Phenogenomics: developing towards translation research (by MEYS and ESIF, OP RDE CZ.02.1.01/0.0/0.0/16_013/0001789), BCH viral core for AAV production. The collaboration between Masaryk University and Karolinska Institutet (KI-MU program), was co-financed by the European Social Fund and the state budget of the Czech Republic (CZ.1.07/2.3.00/20.0180). Funding to the VB lab was obtained from Neuron Fund for Support of Science (23/2016), and Czech Science Foundation (GA17- 16680S). Work in the EA lab was supported by the Swedish Research Council (VR projects: DBRM, 2011-3116, 2011-3318 and 2016-01526), Swedish Foundation for Kaiser et al.,Strategic Research (SRL program and SLA SB16-0065), European Commission (NeuroStemcellRepair), Karolinska Institutet (SFO Strat Regen, Senior grant 2018), Hjärnfonden (FO2015:0202 and FO2017-0059) and Cancerfonden (CAN 2016/572) foundations. KK was supported by Masaryk University (MUNI/E/0965/2016). RvA acknowledges funding support from the University of Amsterdam (MacGillavry fellowship), KWF Kankerbestrijding (Dutch Cancer Society, career development award ANW 2013-6057) and NWO (Netherlands Science Foundation, VIDI 864.13.002). Work in the OM lab is supported by the Czech Science Foundation (18- 00514S). ZK acknowledges funding support from GACR 18-20759S. RA Barker is supported by an NIHR funded Biomedical Research Centre at Cambridge University Hospital and the WT-MRC Cambridge Stem Cell Institute. The Lehtinen laboratory was supported by the Reagan Sloane Shanley Research Internship (ND), OFD/BTREC/CTREC Faculty Development Fellowship Award (RMF), NIH R01 NS088566 (MKL), the New York Stem Cell Foundation (MKL); and BCH IDDRC 1U54HD090255. MK Lehtinen is a New York Stem Cell Foundation – Robertson Investigator.