Comparative approaches to understanding thyroid hormone regulation of neurogenesis

International audienceThyroid hormone (TH) signalling, an evolutionary conserved pathway, is crucial for brain function and cognition throughout life, from early development to ageing. In humans, TH deficiency during pregnancy alters offspring brain development, increasing the risk of cognitive disorders. How TH regulates neurogenesis and subsequent behaviour and cognitive functions remains a major research challenge. Cellular and molecular mechanisms underlying TH signalling on proliferation, survival, determination, migration, differentiation and maturation have been studied in mammalian animal models for over a century. However, recent data show that THs also influence embryonic and adult neurogenesis throughout vertebrates (from mammals to teleosts). These latest observations raise the question of how TH availability is controlled during neurogenesis and particularly in specific neural stem cell populations. This review deals with the role of TH in regulating neurogenesis in the developing and the adult brain across different vertebrate species. Such evo-devo approaches can shed new light on (i) the evolution of the nervous system and (ii) the evolutionary control of neurogenesis by TH across animal phyla. We also discuss the role of thyroid disruptors on brain development in an evolutionary context

The pyriproxyfen metabolite, 4 '-OH-PPF, disrupts thyroid hormone signaling in neural stem cells, modifying neurodevelopmental genes affected by ZIKA virus infection.*

North-Eastern Brazil saw intensive application of the insecticide pyriproxyfen (PPF) during the microcephaly outbreak caused by the Zika virus (ZIKV). ZIKV requires the neural RNA-binding protein Musashi-1 to replicate. Thyroid hormone (TH) represses MSI1. PPF is a suspected TH disruptor. We hypothesized that co-exposure to the main metabolite of PPF, 4′–OH–PPF, could exacerbate ZIKV effects through increased MSI1 expression. Exposing an in vivo reporter model, Xenopus laevis, to 4′–OH–PPF decreased TH signaling and increased msi1 mRNA and protein, confirming TH-antagonistic properties. Next, we investigated the metabolite's effects on mouse subventricular zone-derived neural stem cells (NSCs). Exposure to 4′–OH–PPF dose-dependently reduced neuroprogenitor proliferation and dysregulated genes implicated in neurogliogenesis. The highest dose induced Msi1 mRNA and protein, increasing cell apoptosis and the ratio of neurons to glial cells. Given these effects of the metabolite alone, we considered if combined infection with ZIKV worsened neurogenic events. Only at the fourth and last day of incubation did co-exposure of 4′–OH–PPF and ZIKV decrease viral replication, but viral RNA copies stayed within the same order of magnitude. Intracellular RNA content of NSCs was decreased in the combined presence of 4′–OH–PPF and ZIKV, suggesting a synergistic block of transcriptional machinery. Seven out of 12 tested key genes in TH signaling and neuroglial commitment were dysregulated by co-exposure, of which four were unaltered when exposed to 4′–OH–PPF alone. We conclude that 4′–OH–PPF is an active TH-antagonist, altering NSC processes known to underlie correct cortical development. A combination of the TH-disrupting metabolite and ZIKV could aggravate the microcephaly phenotype

Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain

International audienceIn the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal versus glial fate are largely unknown. Here we report that a thyroid hormone (T 3)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation. After demyelination, oligodendrocytes derived from these newly-formed progenitors provide functional remyelination, restoring normal conduction. The cellular basis for neuronal versus glial determination in progenitors involves asymmetric partitioning of EGFR and TRa1, expression of which favor glio-and neuro-genesis, respectively. Moreover, EGFR + oligodendrocyte progenitors, but not neuroblasts, express high levels of a T 3-inactivating deiodinase, Dio3. Thus, TRa absence with high levels of Dio3 provides double-pronged blockage of T 3 action during glial lineage commitment. These findings not only transform our understanding of how T 3 orchestrates adult brain lineage decisions, but also provide potential insight into demyelinating disorders

Maternal Diets Trigger Sex-Specific Divergent Trajectories of Gene Expression and Epigenetic Systems in Mouse Placenta

Males and females responses to gestational overnutrition set the stage for subsequent sex-specific differences in adult onset non communicable diseases. Placenta, as a widely recognized programming agent, contibutes to the underlying processes. According to our previous findings, a high-fat diet during gestation triggers sex-specific epigenetic alterations within CpG and throughout the genome, together with the deregulation of clusters of imprinted genes. We further investigated the impact of diet and sex on placental histology, transcriptomic and epigenetic signatures in mice. Both basal gene expression and response to maternal high-fat diet were sexually dimorphic in whole placentas. Numerous genes showed sexually dimorphic expression, but only 11 genes regardless of the diet. In line with the key role of genes belonging to the sex chromosomes, 3 of these genes were Y-specific and 3 were X-specific. Amongst all the genes that were differentially expressed under a high-fat diet, only 16 genes were consistently affected in both males and females. The differences were not only quantitative but remarkably qualitative. The biological functions and networks of genes dysregulated differed markedly between the sexes. Seven genes of the epigenetic machinery were dysregulated, due to effects of diet, sex or both, including the Y- and X-linked histone demethylase paralogues Kdm5c and Kdm5d, which could mark differently male and female epigenomes. The DNA methyltransferase cofactor Dnmt3l gene expression was affected, reminiscent of our previous observation of changes in global DNA methylation. Overall, this striking sexual dimorphism of programming trajectories impose a considerable revision of the current dietary interventions protocols. © 2012 Gabory et al

Ingenuity pathway analysis for gene responding to HFD: Biological functions in female.

a<p>The first 10 biological categories of function are indicated and function annotation with a significant z-score are detailed.</p>u<p>Upregulated genes. ^dDownregulated genes.</p><p>Underline corresponds to genes deregulated both in female and male placentas.</p

Western blotting with antibodies specific for H3K4me3 and H3K9me3.

<p>was used to determine the degree of lysine-specific methylation, in relationship with Kdm5c/5d (H3K4me3 demethylase) and Kmt1a/1b (H3K9 trimethylases). No sex- or diet-specific signal was observed.</p

Ingenuity pathway analysis for gene responding to HFD: Networks in female.

a<p>Networks with scores ≥25 are indicated. ^bGenes in bold are included in our datasets.</p>u<p>Upregulated genes. ^dDownregulated genes.</p><p>Underline corresponds to genes deregulated both in female and male placentas.</p