ZFP423 regulates early patterning and multiciliogenesis in the hindbrain choroid plexus

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, encoding 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 (RP), from which the IV ventricle ChP arises, and, later, in mesenchymal cells giving rise to the stroma and leptomeninges. 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, Otx2); 2) shows a perturbed expression of signaling pathways previously unexplored in hChP patterning (Wnt3); 3) displays a lack of multiciliated epithelial cells and a profound dysregulation of master genes of multiciliogenesis (Gmnc). Our results propose Zfp423 as a master gene and one of the earliest known determinants of hChP development.