The transcription factor Otx2 regulates choroid plexus development and function

Abstract

SUMMARYThe choroid plexuses (ChPs) are the main regulators of cerebrospinal fluid (CSF) composition and thereby also control the composition of a principal source of signaling molecules that is in direct contact with neural stem cells in the developing brain. The regulators of ChP development mediating the acquisition of a fate that differs from the neighboring neuroepithelial cells are poorly understood. Here, we demonstrate in mice a crucial role for the transcription factor Otx2 in the development and maintenance of ChP cells. Deletion of Otx2 by the Otx2-CreERT2 driver line at E9 resulted in a lack of all ChPs, whereas deletion by the Gdf7-Cre driver line affected predominately the hindbrain ChP, which was reduced in size, primarily owing to an increase in apoptosis upon Otx2 deletion. Strikingly, Otx2 was still required for the maintenance of hindbrain ChP cells at later stages when Otx2 deletion was induced at E15, demonstrating a central role of Otx2 in ChP development and maintenance. Moreover, the predominant defects in the hindbrain ChP mediated by Gdf7-Cre deletion of Otx2 revealed its key role in regulating early CSF composition, which was altered in protein content, including the levels of Wnt4 and the Wnt modulator Tgm2. Accordingly, proliferation and Wnt signaling levels were increased in the distant cerebral cortex, suggesting a role of the hindbrain ChP in regulating CSF composition, including key signaling molecules. Thus, Otx2 acts as a master regulator of ChP development, thereby influencing one of the principal sources of signaling in the developing brain, the CSF.

Astrocyte reactivity after brain injury—: The role of galectins 1 and 3

“…Consistent with previous microarray analyses (Beckervordersandforth et al, 2010; Johansson et al, 2013; Ninkovic et al, 2013; Pinto et al, 2009, 2008; Stahl et al, 2013; Walcher et al, 2013), quantitative reverse transcription polymerase chain reaction (qRT‐PCR) confirmed the changes observed in the microarray (Fig. 3D), including the strongly upregulated genes Lgals1 (lectin, galactoside‐binding, soluble, 1) and Lgals3 (lectin, galactoside‐binding, soluble, 3) (40× and 10×, respectively).…”

Molecular anatomy and functions of the choroidal blood-cerebrospinal fluid barrier in health and disease

“…The Otx2 gene, which encodes a transcription factor containing a homeodomain important for the development of the CNS, plays a major role in the formation of the plexuses. Indeed, the four plexuses are absent after conditional deletion of this gene at E9 in mice [64]. Both proliferation and differentiation of choroidal epithelial cells are dependent on Notch signalling and neurogenin2 [60].…”

“…By dynamically altering its secretome in response to input signals, the choroid plexus modulates stem cell behaviour in adult neural stem cell niches, can affect physiology and contribute to pathology function is key to normal brain development, as inherited or acquired choroidal folate transport defects induce cerebral folate deficiency that translate into severe childhood neurodegenerative diseases [54,142], and may be a main contributor to the encephalopathy associated with the Kearns Sayre syndrome [141]. Due to the flow of the CSF through the ventricular system, factors can exert long-range, as well as regionally distinct effects, depending on local concentration gradients of individual factors and the repertoire of receptors and modulators expressed by the responding cells [64].…”

Multiple roles of Ulk4 in neurogenesis and brain function

“…23 Normal production and circulation of the CSF are known to be crucial for proper brain development. 24,25 For example, Wnt4 and Wnt modulator Tgm2 are regulated by Otx2, a master regulator of choroid plexus development which produces CSF. 24 We showed recently that Ulk4 is essential for ciliogenesis and CSF flow.…”

“…24,25 For example, Wnt4 and Wnt modulator Tgm2 are regulated by Otx2, a master regulator of choroid plexus development which produces CSF. 24 We showed recently that Ulk4 is essential for ciliogenesis and CSF flow. 26 Ependymal layer constitutes polarized cells with motile cilia projecting to ventricles, and the planar cell polarity cadherins Celsr2 and Celsr3 are shown to regulate basal body orientation at the foot of cilia.…”