Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain
- Sorbonne Universités, Muséum d’Histoire Naturelle, France
- INSERM U1128, France
- Université Paris Descartes, France
- Instituto de Ciencias Biomédicas, Facultad de Ciencias de la Salud, Universidad Autónoma de Chile, Chile
- Sorbonne Universités UPMC Univ Paris 06, France
- Institute of Experimental Medicine, Hungarian Academy of Sciences, Hungary
- Tufts Medical Center, United States
- AP-HP, Hôpital Pitié-Salpêtrière, France
Figures
Figure 1 with 3 supplements
Hypothyroidism during demyelination favors oligodendrogenesis.
(A) Experimental procedure: Cuprizone (CPZ) was added to the diet for 6 weeks (d0 to d42) and a T3-free window applied for one month, two weeks after onset of CPZ treatment (d14 to d42). Three …
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Figure 1—source data 1
Hypothyroidism during demyelination favors oligodendrogenesis.
- https://doi.org/10.7554/eLife.29996.006
Figure 1—figure supplement 1
A T3-free window during CPZ demyelination increases remyelination.
(A) Quantification of OLIG2+ oligodendrocyte progenitors in the SVZ and in the corpus callosum following four weeks of hypothyroidism (without cuprizone). (B) Quantification of MBP mean fluorescence …
Figure 1—figure supplement 2
SVZ-OPCs are recruited to the corpus callosum following a demyelinating insult.
Coronal sections showing GFP + cells (green) 20d after injection of CMV-eGFP-expressing lentiviral particles into the adult SVZ. GFP + cells are mainly confined to the SVZ of CTL (n = 3) and EuCPZ …
Figure 1—figure supplement 3
(A–B) Mice received T3/T4 pulses during the recuperation phase.
(A) Quantification of the g-ratio in control (CTL), euthyroid-CPZ (EuCPZ) and hypothyroid-CPZ (HypoCPZ) (mean ± SEM, n > 100 per group. ***p<0.001, Kruskal-Wallis test followed by a Dunn’s post-hoc …
Figure 2 with 1 supplement
Hypothyroidism during demyelination induces functional recovery of myelinated axons.
(A) Differential interference contrast image showing a brain slice (coronal view) from the CPZ group. CC = corpus callosum, arrowhead indicates the demyelinated lesion. (B) CAPs obtained following …
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Figure 2—source data 1
Hypothyroidism during demyelination induces functional recovery of myelinated axons.
- https://doi.org/10.7554/eLife.29996.009
Figure 2—figure supplement 1
Differential interference contrast image (coronal view) of recorded acute slices from control, EuCPZ and HypoCPZ groups.
CC = corpus callosum. Scale bar: 200 µm.
Figure 3 with 1 supplement
T3/TRα1 signaling is excluded from the oligodendroglial lineage and represses EGFR expression in adult SVZ.
(A–D) Coronal sections of adult SVZ treated for immunohistochemistry, TRα1 (red in A and B) is not expressed in OLIG2+ (grey) oligodendrocyte progenitors (A), nor SOX10+ (green) oligodendrocyte …
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Figure 3—source data 1
T3/TRα1 signaling is excluded from the oligodendroglial lineage and represses EGFR expression in adult SVZ.
- https://doi.org/10.7554/eLife.29996.012
Figure 3—figure supplement 1
TRα1 signalling is associated with a neuronal fate in vitro and in vivo.
(A) Analysis of TRα1 (β-Gal) and OLIG2 fluorescent signals. Two distinct cell populations are discriminated: a population of OLIG2high/TRα1low (blue circle) is clustered as a separate population of …
Figure 4
Asymmetric TRα1/EGFR segregation in the adult SVZ.
(A–F) TRα1 and EGFR segregate asymmetrically in the adult SVZ in vivo. Coronal sections of WT adult mouse brain across the lateral ventricles were immunostained with anti-TRα1 (red) and/or anti-EGFR …
Figure 5 with 2 supplements
Cell-specific Dio3 expression in the adult SVZ.
(A–C) The inactivating deiodinase, Dio3, is detected in SVZ-derived OPCs, but not in DCX+ neuroblasts. (A) Dio3 (grey) is detected in NSC identified by co-expression of SOX2 (red) and Nestin (green) …
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Figure 5—source data 1
Cell-specific Dio3 expression in the adult SVZ.
- https://doi.org/10.7554/eLife.29996.017
Figure 5—figure supplement 1
Expression of the inactivating deiodinase, Dio3, excludes TH signalling from NSC, progenitors and oligodendrocyte progenitors.
(A) The SVZ from nestin:GFP adult mice was double-stained with anti-GFAP (red) and anti-Dio3 (grey) antibodies. Note that Dio3 is highly expressed in the radial process of Nestin+ and GFAP+ NSC …
Figure 5—figure supplement 2
(A and B) SVZ tissues were sampled from WT adult mice for neurosphere culture.
After plating, dissociated cells from neurospheres were induced to differentiate in presence of a short pulse of T3 at four different concentrations (0, 1, 10 and 50 nM). One week after initial …
Figure 6
Modulation of timing of thyroid hormone (T3) availability in the adult brain modifies cell fate decisions (neuronal versus oligodendroglial fate choice) in the sub-ventricular zone (SVZ).
T3 through its nuclear receptor, TRα1, favours progenitor commitment toward a neuroblast phenotype. In contrast, a transient lack of T3 (T3-free window) increases numbers of oligodendrocyte …
Additional files
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Transparent reporting form
- https://doi.org/10.7554/eLife.29996.019
