ABSTRACT
The choroid plexus (ChP) is a secretory tissue that produces cerebrospinal fluid (CSF) secreted into the ventricular system. It is a monolayer of secretory, multiciliated epithelial cells derived from neuroepithelial progenitors and overlying a stroma of mesenchymal cells of mesodermal origin. Zfp423, which encodes a Kruppel-type zinc-finger transcription factor essential for cerebellar development and mutated in rare cases of cerebellar vermis hypoplasia/Joubert syndrome and other ciliopathies, is expressed in the hindbrain roof plate, from which the IV ventricle ChP arises, and, later, in mesenchymal cells, which give rise to the stroma and leptomeninges. Mouse Zfp423 mutants display a marked reduction of the hindbrain ChP (hChP), which: (1) fails to express established markers of its secretory function and genes implicated in its development and maintenance (Lmx1a and Otx2); (2) shows a perturbed expression of signaling pathways previously unexplored in hChP patterning (Wnt3); and (3) displays a lack of multiciliated epithelial cells and a profound dysregulation of master genes of multiciliogenesis (Gmnc). Our results propose that Zfp423 is a master gene and one of the earliest known determinants of hChP development.
Footnotes
Author contributions
Conceptualization: F.C., L.C., G.G.C.; Methodology: F.C., L.C., F.V., P.P., G.G.C.; Formal analysis: F.C., M.R., L.M., O.C., G.G.C.; Investigation: F.C., L.C., F.V., P.P., G.G.C.; Data curation: M.R., L.M.; Writing - original draft: F.C., L.C., G.G.C.; Writing - review & editing: F.C., L.C., O.C., G.G.C.; Supervision: F.C., L.C.; Funding acquisition: O.C., G.G.C.
Funding
This work was mostly funded by the Fondazione Telethon (GGP13146 to G.G.C.); an additional contribution was provided by the Ministero della Salute Ricerca Finalizzata 2011 (PE-2011-02347716 to O.C.). S.W. was supported by the National Institutes of Health Intramural Research Program, Center for Cancer Research, National Cancer Institute. Deposited in PMC for release after 12 months.
Data availability
RNA-seq data reported in this publication have been deposited in GEO under accession number GSE160300.
