Abstract:Choroid plexus epithelial cells produce and secrete transthyretin (TTR). TTR binds and distributes thyroid hormone (TH) to brain cells via the cerebrospinal fluid. The adult murine subventricular zone (SVZ) is in close proximity to the choroid plexus. In the SVZ, TH determines neural stem cell (NSC) fate towards a neuronal or a glial cell. We investigated whether the loss of TTR also disrupted NSC fate choice. Our results show a decreased neurogenic versus oligodendrogenic balance in the lateroventral SVZ of T… Show more
“…This discrepancy between mRNA and protein expressions can be explained by a longer half-life of both THT proteins, as previously observed in rats ( Wittmann et al., 2015 ). Similarly, we previously demonstrated that Ttr transcripts are expressed in the SVZ of adult mice, whereas the protein is not detected by IHC ( Vancamp et al., 2019 ). Figure 2 TH Signaling Components Are Dynamically Expressed in Neuronal Lineage Cells within the Adult SVZ (A) Schematic representation of the markers used to quantify TH signaling components mRNA expression levels in quiescent and activated NSCs (CD133+EGFR), TACs (EGFR+), NPCs (EGFR+CD24+) and neuroblasts (CD24+) from FACS-sorted SVZ cells of five adult WT male mice.…”
Section: Resultsmentioning
confidence: 58%
“…This discrepancy between mRNA and protein expressions can be explained by a longer half-life of both THT proteins, as pre-viously observed in rats (Wittmann et al, 2015). Similarly, we previously demonstrated that Ttr transcripts are expressed in the SVZ of adult mice, whereas the protein is not detected by IHC (Vancamp et al, 2019).…”
Section: The Th Signaling Pathway Is Dynamically Regulated During Neumentioning
confidence: 61%
“…To be more precise, only DKO mice display a strong decrease of both T 3 and T 4 contents in the brain as a consequence of a highly reduced T 4 and T 3 transport across brain barriers ( Mayerl et al., 2014 ). This allowed us to compare the cellular effects underlying the absence of both transporters with our previous well-established data obtained after induction of adult-onset hypothyroidism ( Gothié et al., 2017a ; Remaud et al., 2017 ; Vancamp et al., 2019 ).…”
Summary
Adult neural stem cell (NSC) generation in vertebrate brains requires thyroid hormones (THs). How THs enter the NSC population is unknown, although TH availability determines proliferation and neuronal versus glial progenitor determination in murine subventricular zone (SVZ) NSCs. Mice display neurological signs of the severely disabling human disease, Allan-Herndon-Dudley syndrome, if they lack both MCT8 and OATP1C1 transporters, or MCT8 and deiodinase type 2. We analyzed the distribution of MCT8 and OATP1C1 in adult mouse SVZ. Both are strongly expressed in NSCs and at a lower level in neuronal cell precursors but not in oligodendrocyte progenitors. Next, we analyzed
Mct8
/
Oatp1c1
double-knockout mice, where brain uptake of THs is strongly reduced. NSC proliferation and determination to neuronal fates were severely affected, but not SVZ-oligodendroglial progenitor generation. This work highlights how tight control of TH availability determines NSC function and glial-neuron cell-fate choice in adult brains.
“…This discrepancy between mRNA and protein expressions can be explained by a longer half-life of both THT proteins, as previously observed in rats ( Wittmann et al., 2015 ). Similarly, we previously demonstrated that Ttr transcripts are expressed in the SVZ of adult mice, whereas the protein is not detected by IHC ( Vancamp et al., 2019 ). Figure 2 TH Signaling Components Are Dynamically Expressed in Neuronal Lineage Cells within the Adult SVZ (A) Schematic representation of the markers used to quantify TH signaling components mRNA expression levels in quiescent and activated NSCs (CD133+EGFR), TACs (EGFR+), NPCs (EGFR+CD24+) and neuroblasts (CD24+) from FACS-sorted SVZ cells of five adult WT male mice.…”
Section: Resultsmentioning
confidence: 58%
“…This discrepancy between mRNA and protein expressions can be explained by a longer half-life of both THT proteins, as pre-viously observed in rats (Wittmann et al, 2015). Similarly, we previously demonstrated that Ttr transcripts are expressed in the SVZ of adult mice, whereas the protein is not detected by IHC (Vancamp et al, 2019).…”
Section: The Th Signaling Pathway Is Dynamically Regulated During Neumentioning
confidence: 61%
“…To be more precise, only DKO mice display a strong decrease of both T 3 and T 4 contents in the brain as a consequence of a highly reduced T 4 and T 3 transport across brain barriers ( Mayerl et al., 2014 ). This allowed us to compare the cellular effects underlying the absence of both transporters with our previous well-established data obtained after induction of adult-onset hypothyroidism ( Gothié et al., 2017a ; Remaud et al., 2017 ; Vancamp et al., 2019 ).…”
Summary
Adult neural stem cell (NSC) generation in vertebrate brains requires thyroid hormones (THs). How THs enter the NSC population is unknown, although TH availability determines proliferation and neuronal versus glial progenitor determination in murine subventricular zone (SVZ) NSCs. Mice display neurological signs of the severely disabling human disease, Allan-Herndon-Dudley syndrome, if they lack both MCT8 and OATP1C1 transporters, or MCT8 and deiodinase type 2. We analyzed the distribution of MCT8 and OATP1C1 in adult mouse SVZ. Both are strongly expressed in NSCs and at a lower level in neuronal cell precursors but not in oligodendrocyte progenitors. Next, we analyzed
Mct8
/
Oatp1c1
double-knockout mice, where brain uptake of THs is strongly reduced. NSC proliferation and determination to neuronal fates were severely affected, but not SVZ-oligodendroglial progenitor generation. This work highlights how tight control of TH availability determines NSC function and glial-neuron cell-fate choice in adult brains.
“…Notum, a secreted extracellular suppressor of Wnt ligands, displays SVZ-subdomain-specific expression [180], raising an interesting possibility of spatially-restricted regulation of Wnt pathway activation via localized deactivation of Wnt ligands, which were previously shown to be secreted from the CP into CSF [62,111]. Corroborating these findings, transthyretin (TTR), a thyroid hormone transporter predominantly produced by the CP [112], exhibits a gender-specific role in the control of neurogenesis in the SVZ that is restricted to a specific subdomain of the SVZ [181], which is in line with the gender-based differences in CP-derived TTR levels detected in the CSF [71,182]. Molecular heterogeneity linked to the receptor repertoire can be also observed between SVZ and SGZ, indicating intrinsic differences in the sensitivity of adult germinal centres to signalling factors presented via CSF [183,184].…”
Section: The Target Brain Regions Of Cp-csf Signallingmentioning
Cerebrospinal fluid (CSF) is the liquid that fills the brain ventricles. CSF represents not only a mechanical brain protection but also a rich source of signalling factors modulating diverse processes during brain development and adulthood. The choroid plexus (CP) is a major source of CSF and as such it has recently emerged as an important mediator of extracellular signalling within the brain. Growing interest in the CP revealed its capacity to release a broad variety of bioactive molecules that, via CSF, regulate processes across the whole central nervous system (CNS). Moreover, CP has been also recognized as a sensor, responding to altered composition of CSF associated with changes in the patterns of CNS activity. In this review, we summarize the recent advances in our understanding of the CP as a signalling centre that mediates long-range communication in the CNS. By providing a detailed account of the CP secretory repertoire, we describe how the CP contributes to the regulation of the extracellular environment—in the context of both the embryonal as well as the adult CNS. We highlight the role of the CP as an important regulator of CNS function that acts via CSF-mediated signalling. Further studies of CP–CSF signalling hold the potential to provide key insights into the biology of the CNS, with implications for better understanding and treatment of neuropathological conditions.
“…Data on the regulation of TH metabolism in NSCs almost exclusively originates from rodent studies. MCT8 and OATP1C1 mediate TH uptake at the endothelial cells of the rodent BBB as they do in other brain regions ( Mayerl et al, 2014 ; Vatine et al, 2017 ), while TTR provides at least a part of T 4 to SVZ-NSCs via the CSF ( Vancamp et al, 2019 ; Alshehri et al, 2020 ). It is currently unknown which transporters facilitate TH uptake into SVZ-NSCs themselves.…”
Section: The Potential Of Thyroid Hormone As a Pro-repair Cuementioning
Neurodegenerative diseases are characterized by chronic neuronal and/or glial cell loss, while traumatic injury is often accompanied by the acute loss of both. Multipotent neural stem cells (NSCs) in the adult mammalian brain spontaneously proliferate, forming neuronal and glial progenitors that migrate toward lesion sites upon injury. However, they fail to replace neurons and glial cells due to molecular inhibition and the lack of pro-regenerative cues. A major challenge in regenerative biology therefore is to unveil signaling pathways that could override molecular brakes and boost endogenous repair. In physiological conditions, thyroid hormone (TH) acts on NSC commitment in the subventricular zone, and the subgranular zone, the two largest NSC niches in mammals, including humans. Here, we discuss whether TH could have beneficial actions in various pathological contexts too, by evaluating recent data obtained in mammalian models of multiple sclerosis (MS; loss of oligodendroglial cells), Alzheimer's disease (loss of neuronal cells), stroke and spinal cord injury (neuroglial cell loss). So far, TH has shown promising effects as a stimulator of remyelination in MS models, while its role in NSC-mediated repair in other diseases remains elusive. Disentangling the spatiotemporal aspects of the injury-driven repair response as well as the molecular and cellular mechanisms by which TH acts, could unveil new ways to further exploit its proregenerative potential, while TH (ant)agonists with cell type-specific action could provide safer and more target-directed approaches that translate easier to clinical settings.
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