Proliferation and migration during adult neurogenesis are regulated by a microenvironment of signaling molecules originating from local vasculature, from CSF produced by the choroid plexus, and from local supporting cells including astrocytes. Here, we focus on the function of OTX2 homeoprotein transcription factor in the mouse adult ventricular-subventricular zone (V-SVZ), which generates olfactory bulb neurons. We find that OTX2 secreted by choroid plexus is transferred to the supporting cells of the V-SVZ and rostral migratory stream. Deletion of Otx2 in choroid plexus affects neuroblast migration and reduces the number of olfactory bulb newborn neurons. Adult neurogenesis was also decreased by expressing secreted single-chain antibodies to sequester OTX2 in the CSF, demonstrating the importance of non-cell-autonomous OTX2. We show that OTX2 activity modifies extracellular matrix components and signaling molecules produced by supporting astrocytes. Thus, we reveal a multilevel and non-cell-autonomous role of a homeoprotein and reinforce the choroid plexus and astrocytes as key niche compartments affecting adult neurogenesis.

Proliferation and migration during adult neurogenesis are regulated by a microenvironment originating from local vasculature, from cerebrospinal fluid produced by the choroid plexus, and from local supporting cells including astrocytes. Here, we focus on the function of Otx2 homeoprotein transcription factor in the adult subventricular zone which generates olfactory bulb neurons. We find that Otx2 secreted by choroid plexus is transferred to supporting cells of the subventricular zone and rostral migratory stream. Deletion of Otx2 in choroid plexus reduces the number of olfactory bulb newborn neurons and modifies extracellular matrix components produced by astrocytes. By expressing secreted single-chain antibodies to sequester Otx2 in the cerebrospinal fluid, we obtain similar results, demonstrating the importance of non-cell autonomous Otx2 in adult neurogenesis and suggesting a pivotal role for astrocytes. By using in vitro astrocytes co-cultured with neurospheres, we show that Otx2 down-regulates tenascin-C expression and subsequently modifies neuroblast migration. Thus, we reveal a multi-level and non-cell autonomous role of a homeoprotein, and reinforce the idea of the choroid plexus as a key niche compartment affecting adult neurogenesis.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/243659 doi: bioRxiv preprint first posted online Jan. 5, 2018; 2 Introduction Neurogenesis in the adult mouse brain provides continuous replacement of interneurons in olfactory bulbs (OB) and is important for olfaction-based learning 1 . Neural stem cells, located in the adult subventricular zone (aSVZ) lining the lateral cerebral ventricles, give rise to progenitor cells (neuroblasts) that migrate though the rostral migratory stream (RMS) to reach the OB where they differentiate as interneurons and integrate into the network. The RMS is composed of a compacted neuroblast network forming chains that migrate along blood vessels and are surrounded by astrocytic processes 2,3 . While it is clear that RMS-associated astrocytes interact with neuroblasts 4 , the role of astrocytes for neuroblast migration is not well known. Astrocytes are also located in the aSVZ and are thought to play a role as supporting cells for regulating the neurogenic niche microenvironment 5 . The niche is further influenced by extrinsic factors coming from local vasculature and the cerebrospinal fluid (CSF) 6 . Furthermore, neural stem cells interact directly with both vasculature and CSF 7 . Indeed, it has been shown that molecules within the CSF can control aSVZ neurogenesis by regulating cell proliferation 8 or migration 9 . Homeoproteins are key regulators of neurogenesis both during embryogenesis and adult neurogenesis 10,11 . This class of transcription factors have the property to act both cellautonomously and non-cell-autonomously after secretion and internalization in target cells. The Otx2 homeoprotein is exp...

1. The role of growth hormone (GH) in cardiac remodelling and function in chronic and persistent pressure overload-induced left ventricular hypertrophy has not been defined. The aim of the present study was to assess short-term GH treatment on left ventricular function and remodelling in rats with chronic pressure overload-induced hypertrophy. 2. Twenty-six weeks after induction of ascending aortic stenosis (AAS), rats were treated with daily subcutaneous injections of recombinant human GH (1 mg/kg per day; AAS-GH group) or saline (AAS-P group) for 14 days. Sham-operated animals served as controls. Left ventricular function was assessed by echocardiography before and after GH treatment. Myocardial fibrosis was evaluated by histological analysis. 3. Before GH treatment, AAS rats presented similar left ventricular function and structure. Treatment of rats with GH after the AAS procedure did not change bodyweight or heart weight, both of which were higher in the AAS groups than in the controls. After GH treatment, posterior wall shortening velocity (PWSV) was lower in the AAS-P group than in the control group. However, in the AAS-GH group, PWSV was between that in the control and AAS-P groups and did not differ significantly from either group. Fractional collagen (% of total area) was significantly higher in the AAS-P and AAS-GH groups compared with control (10.34 +/- 1.29, 4.44 +/- 1.37 and 1.88 +/- 0.88%, respectively; P < 0.05) and was higher still in the AAS-P group compared with the AAS-GH group. 4. The present study has shown that short-term administration of GH to rats with chronic pressure overload-induced left ventricular hypertrophy induces cardioprotection by attenuating myocardial fibrosis.

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Astrocytes are the most abundant glial cells of the central nervous system and have recently been recognized as crucial in the regulation of brain immunity. In most neuropathological conditions, astrocytes are prone to a radical phenotypical change called reactivity, which plays a key role in astrocyte contribution to neuroinflammation. However, how astrocytes regulate brain immunity in healthy conditions is an understudied question. One of the astroglial molecule involved in these regulations might be Connexin 43 (Cx43), a gap junction protein highly enriched in astrocyte perivascular endfeet-terminated processes forming the glia limitans. Indeed, Cx43 deletion in astrocytes (Cx43KO) promotes a continuous immune recruitment and an autoimmune response against an astrocyte protein, without inducing any brain lesion. To investigate the molecular basis of this unique immune response, we characterized the polysomal transcriptome of hippocampal astrocytes deleted for Cx43. Our results demonstrate that, in the absence of Cx43, astrocytes adopt an atypical reactive status with no change in most canonical astrogliosis markers, but with an upregulation of molecules promoting immune recruitment, complement activation as well as anti-inflammatory processes. Intriguingly, while several of these upregulated transcriptional events suggested an activation of the γ-interferon pathway, no increase in this cytokine or activation of related signaling pathways were found in Cx43KO. Finally, deletion of astroglial Cx43 was associated with the upregulation of several angiogenic factors, consistent with an increase in microvascular density in Cx43KO brains. Collectively, these results strongly suggest that Cx43 controls immunoregulatory and angiogenic properties of astrocytes.

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Elevated amyloid precursor protein (APP) expression in the choroid plexus suggests an important role for extracellular APP metabolites such as sAPPα in cerebrospinal fluid. Despite widespread App brain expression, we hypothesized that specifically targeting choroid plexus expression could alter animal physiology. Through various genetic and viral approaches in the adult mouse, we show that choroid plexus APP levels significantly impact proliferation in both subventricular zone and hippocampus dentate gyrus neurogenic niches. Given the role of Aβ peptides in Alzheimer disease pathogenesis, we also tested whether favoring the production of Aβ in choroid plexus could negatively affect niche functions. After AAV5-mediated long-term expression of human mutated APP specifically in the choroid plexus of adult wild-type mice, we observe reduced niche proliferation, reduced hippocampus APP expression, behavioral defects in reversal learning, and deficits in hippocampal long-term potentiation. Our findings highlight the unique role played by the choroid plexus in regulating brain function and suggest that targeting APP in choroid plexus may provide a means to improve hippocampus function and alleviate disease-related burdens.

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.