Loss of Elp3 induces postnatal hydrocephalus by inducing endoplasmic reticulum stress and dysregulation of Notch signaling
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1
GIGA-Neurosciences, University of Liège, Belgium
Ependymal cells line the ventricle of the adult brain and bear multiple motile cilia at their apical surface. Planar polarization of ependymal cells determines the orientation of motile cilia whose coordinated beating drives directional cerebrospinal fluid (CSF) flow. Defects in planar polarity establishment and impaired ciliogenesis have been associated with hydrocephalus and developmental abnormalities. Although several proteins have been identified as planar cell polarity core components, the precise regulation of the establishment of ependymal planar cell polarity and cilium assembly during cortex development remain poorly understood.
Here, using a conditional knock-out mouse model, we showed that a deletion of Elp3, the catalytic subunit of the Elongator complex, in the embryonic telencephalon disrupts the coordinated motile cilia beating and the cerebrospinal fluid flow, leading to enlarged ventricles and postnatal hydrocephaly. Indeed, Elp3 depletion impairs the rotational and translational polarities of ependymal motile cilia, as well as the organization of ciliary tufts at the surface of the lateral wall. Ependymal cells are derived from embryonic radial glial cells, where Elp3 is also required for the coordinated planar polarity and the growth of the primary cilium. The primary cilium has been suggested to participate in the organization of ependymal cells planar polarization and we showed that loss of Elongator activity leads to the accumulation of misfolded proteins that trigger endoplasmic reticulum stress and activate the unfolded protein response. This in turn inhibits Notch signaling and impairs primary ciliogenesis. These concomitant defects in ciliogenesis and planar polarity of ependymal cells perturb the coordinated beating of motile cilia, leading to impaired CSF flow and severe hydrocephalus.
Keywords:
Hydrocephalus,
elongator complex,
Endoplasmic eeticulum stress,
cortex development,
ependymal cells
Conference:
Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.
Presentation Type:
e-posters
Topic:
NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE
Citation:
Laguesse
S
(2019). Loss of Elp3 induces postnatal hydrocephalus by inducing endoplasmic reticulum stress and dysregulation of Notch signaling.
Front. Neurosci.
Conference Abstract:
Belgian Brain Congress 2018 — Belgian Brain Council.
doi: 10.3389/conf.fnins.2018.95.00024
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Received:
13 Aug 2018;
Published Online:
17 Jan 2019.
*
Correspondence:
Dr. Sophie Laguesse, GIGA-Neurosciences, University of Liège, Liege, Belgium, sophie.laguesse@hotmail.com