Abstract
The choroid plexus is an important blood barrier that secretes cerebrospinal fluid, which essential for embryonic brain development and adult brain homeostasis. The OTX2 homeoprotein is a transcription factor that is critical for choroid plexus development and remains highly expressed in adult choroid plexus. Through RNA sequencing analyses of constitutive and conditional knockdown adult mouse models, we reveal putative functional roles for OTX2 in adult choroid plexus function, including cell signaling and adhesion, and show that OTX2 regulates the expression of factors that are secreted into the cerebrospinal fluid, notably transthyretin. We also show that Otx2 expression impacts choroid plexus immune and stress responses, and affects splicing, leading to changes in the mRNA isoforms of proteins that are implicated in the oxidative stress response and DNA repair. Through mass spectrometry analysis of OTX2 protein partners in the choroid plexus, and in known non-cell-autonomous target regions, such as the visual cortex and subventricular zone, we identify putative targets that are involved in cell adhesion, chromatin structure, and RNA processing. Thus, OTX2 retains important roles for regulating choroid plexus function and brain homeostasis throughout life.
Highlights
The choroid plexus (ChP) epithelium is located in the brain ventricles and secretes cerebrospinal fluid (CSF) containing molecules that regulate embryonic brain development and adult brain homeostasis [1]
Through mass spectrometry analysis of OTX2 partners in ChP and non-cell-autonomous target regions [19,20], including the ventricular–subventricular zone (SVZ), rostral migratory stream (RMS), and visual cortex (VCx), we identified putative targets that are involved in cell adhesion, chromatin structure, and RNA processing
The first consisted of 3-month-old Otx2lox/lox mice for the conditional knockdown of Otx2, in the ChP, through intracerebroventricular injections of Cre-Tat recombinant protein, which leads to a ~50% reduction in
Summary
The choroid plexus (ChP) epithelium is located in the brain ventricles and secretes cerebrospinal fluid (CSF) containing molecules that regulate embryonic brain development and adult brain homeostasis [1]. The ventricular system includes the two lateral ventricles (LVs) in each cerebral hemisphere, the central third ventricle of the forebrain diencephalon, and the central fourth ventricle (4V) in the hindbrain. This system is interconnected, allowing for CSF flow throughout, and is connected via the 4V with the central canal of the spinal cord. Embryonic LV and 4V ChP show distinct gene expression patterns [3,4], suggesting different signaling properties. OTX2 is still strongly expressed in the ChP [5], but its role has not been thoroughly investigated
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