Hippocampal Neurogenesis Requires Cell-Autonomous Thyroid Hormone Signaling.

Steffen Mayerl,Charles ffrench-Constant,Heike Heuer

doi:10.1016/j.stemcr.2020.03.014

Abstract

SummaryAdult hippocampal neurogenesis is strongly dependent on thyroid hormone (TH). Whether TH signaling regulates this process in a cell-autonomous or non-autonomous manner remains unknown. To answer this question, we used global and conditional knockouts of the TH transporter monocarboxylate transporter 8 (MCT8), having first used FACS and immunohistochemistry to demonstrate that MCT8 is the only TH transporter expressed on neuroblasts and adult slice cultures to confirm a necessary role for MCT8 in neurogenesis. Both mice with a global deletion or an adult neural stem cell-specific deletion of MCT8 showed decreased expression of the cell-cycle inhibitor P27KIP1, reduced differentiation of neuroblasts, and impaired generation of new granule cell neurons, with global knockout mice also showing enhanced neuroblast proliferation. Together, our results reveal a cell-autonomous role for TH signaling in adult hippocampal neurogenesis alongside non-cell-autonomous effects on cell proliferation earlier in the lineage.

Highlights

Adult hippocampal neurogenesis is a highly orchestrated process with cells passing through distinct stages to generate granule cell neurons (GCNs) throughout life (Beckervordersandforth et al, 2015; Kempermann et al, 2004; Remaud et al, 2014)
This process is initiated from neural stem cells (NSCs) in the subgranular zone (SGZ) that cycle between quiescence and an activated state in which they generate transiently amplifying precursors (TAPs) from which new post-mitotic neurones are formed via an intermediate neuroblast (NB) state
Co-activators or co-repressors are recruited to TR isoforms, including NCOR and SMRT (Astapova and Hollenberg, 2013)

Summary

Introduction

Adult hippocampal neurogenesis is a highly orchestrated process with cells passing through distinct stages to generate granule cell neurons (GCNs) throughout life (Beckervordersandforth et al, 2015; Kempermann et al, 2004; Remaud et al, 2014) This process is initiated from neural stem cells (NSCs) in the subgranular zone (SGZ) that cycle between quiescence and an activated state in which they generate transiently amplifying precursors (TAPs) from which new post-mitotic neurones are formed via an intermediate neuroblast (NB) state. A key question that remains unanswered is whether this effect results from a cell-autonomous requirement for TH signaling within the hippocampal lineage or from an indirect, noncell-autonomous effect resulting from TH function in supporting glial and other cell types. Addressing this is important to identify the necessary cellular targets for therapies designed to treat age-related cognitive decline based on modulated TH signaling

Results

Discussion

Conclusion