Developmental expression of transthyretin and thyroid hormone-convergent effects on murine postnatal SVZ progenitors

Abstract Background Transthyretin (TTR) is a thyroid hormone (TH)-binding protein, that distributes TH through the cerebrospinal fluid to brain cells. Increasing evidence suggests additional cell-autonomous roles in the central nervous system. Here, we investigated Ttr expression and function in the murine subventricular zone, the largest postnatal neural stem cell niche. Methods Public single-cell RNA sequencing datasets were re-analysed to assess Ttr expression across the neurogliogenic lineage. RNAscope and immunohistochemistry were used to evaluate messenger RNA and protein localization. Subventricular zone-derived neurospheres were exposed to exogenous TTR and analysed using single-cell RNA-sequencing and in vitro functional assays. Results Re-analysis of single-cell RNA-sequencing datasets revealed a transcriptional peak of Ttr at postnatal day 7 (P7) across the neurogliogenic lineage. RNAscope confirmed broad but weak mRNA expression in the subventricular zone, whereas immunohistochemistry failed to detect TTR protein, despite robust choroid plexus staining. In P7 subventricular zone-derived neurospheres, exogenous TTR induced a pronounced shift toward more differentiated populations (neuroblasts, oligodendrocyte precursor cells and committed oligodendrocyte precursors), while reducing progenitor proliferation, thereby activating mitochondrial programs, but repressing stemness and proliferation-related pathways. Lower TTR doses reproduced the anti-proliferative effects, and TTR treatment partially mimicked TH-induced outcomes, suggesting partial convergence between TTR- and TH-responsive pathways, despite minimal endogenous TH signalling activity. Conclusion These findings uncover a developmental window of high Ttr expression without detectable protein and reveal that exogenous TTR is sufficient to regulate subventricular zone progenitor behaviour through signalling pathways that at least partially converge with TH responses, although the mechanisms remain unknown. This work expands the functional landscape of TTR and highlights potential relevance for neurodevelopment, as well as neurodegenerative and TH-related disorders.