ELONGATOR CONTROLS THE MATURATION TEMPO OF BRAIN EPENDYMAL CELLS

In this study, we demonstrate that the conditional deletion of Elp3 in the mouse forebrain results in postnatal hydrocephalus, characterized by enlarged brain ventricles. In wild-type animals, ependymal motile cilia are properly oriented to facilitate cerebrospinal fluid (CSF) circulation within the ventricular system. In contrast, Elp3 deficiency in radial glial cells (RGCs) induces endoplasmic reticulum (ER) stress and upregulates the unfolded protein response. This stress response impairs Notch signaling via its poor intracellular maturation and membrane insertion, further disrupting the apical positioning and elongation of the primary cilium in RGCs. These alterations precipitate a premature differentiation of ependymal cells and disrupt the establishment of both rotational and translational planar cell polarity in their motile cilia, ultimately resulting in defective ciliary beating, impaired CSF flow, and hydrocephalus.
Importantly, our findings provide the first mechanistic evidence that the integrity of the primary cilium in mother RGCs is crucial for the proper establishment of planar polarities in maturing ependymal cells. Moreover, our data reveal that tight regulation of the UPR, where Chac1 activity is controlling the intracellular maturation and membrane integration of Notch1 receptors.