Regulatoren der Schilddrüsenhormon-Signalübertragung in der adulten hippocampalen Neurogenese
Zusammenfassung der Projektergebnisse
During my research I addressed the question how exactly thyroid hormones (TH) regulate a process called adult hippocampal neurogenesis - a process that is critical for learning and memory. This was an important question as a link between (adult onset) hypothyroidism and cognitive impairment and depression has been known for decades, but the underlying cellular and molecular abnormalities are very poorly understood. Likewise, previous studies did not elucidate whether TH’s effect on adult hippocampal neurogenesis are cell-autonomous or indirect. To this end, I first performed a comprehensive analysis of the TH signalling pathway during adult hippocampal neurogenesis. By establishing a FACS protocol detecting intracellular markers, I identified the TH transporter Mct8 as the sole transporter expressed at the key stage of neurogenesis - the generation of mature neurons from progenitor cells known as neuroblasts. Then, I confirmed the essential role of Mct8 in this step by using a novel ex vivo slice culture model. Importantly, this method represents a technical advancement as it allows for the pharmacological manipulation of ex vivo neurogenesis in long-lived adult slices. Next, I compared global and conditional Mct8 knockout animals, with the latter mice lacking Mct8 only in adult neurogenic lineages created by crossing Mct8fl/fl mice with those expressing a Nestin-CreERT2 transgene. In both mouse models, I found a reduction in the differentiation capability of neuroblasts as well as a striking reduction in the number of newly formed mature neurons in the hippocampus. These identical effects unequivocally proved a cell-autonomous requirement of TH in the hippocampal neurogenic lineage. Finally, by showing that levels of the cell cycle inhibitor p27KIP1 are reduced in global and cell-specific Mct8 deficiency, I identified a mechanism to how Mct8-mediated thyroid hormone signalling governs neuroblast differentiation. The work presented here shows for the first time the cell-autonomous requirement for TH signalling in hippocampal neurogenesis, with a critical gate-keeper function of Mct8. By linking TH to hippocampal neurogenesis through the regulation of a specific cell cycle inhibitor I have substantially enhanced the current understanding of TH-dependent regulation of adult hippocampal neurogenesis and why hypothyroid patients might suffer from learning difficulties. Moreover, the demonstration that Mct8 is required by neurons may have impacts on the treatment of MCT8-deficient patients. Until now Mct8 was considered to be important mainly at the blood-brain and blood-CSF barriers, and treatment attempts are focussed on restoring TH uptake across brain barriers. My study implies that this may not be completely sufficient and that uptake into neuronal subpopulations may need to be addressed as well. In recognition of the impact of my work, I was awarded the ETA Berlin-Chemie Menarini Young Investigators’ Award at the 42nd annual conference of the European Thyroid Association in 2019.
Projektbezogene Publikationen (Auswahl)
- Familial t(1;11) translocation is associated with disruption of white matter structural integrity and oligodendrocyte-myelin dysfunction. Mol Psychiatry. 2019 Nov;24(11):1641-1654
Vasistha NA, Johnstone M, Barton SK, Mayerl S, Thangaraj Selvaraj B, Thomson PA, Dando O, Grünewald E, Alloza C, Bastin ME, Livesey MR, Economides K, Magnani D, Makedonopolou P, Burr K, Story DJ, Blackwood DHR, Wyllie DJA, McIntosh AM, Millar JK, Ffrench-Constant C, Hardingham GE, Lawrie SM, Chandran S
(Siehe online unter https://doi.org/10.1038/s41380-019-0505-2)
