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A novel tamoxifen-inducible Mct8-CreERT2 mouse model for targeted studies of Mct8-expressing cells and thyroid
Anna Molenaar1,2,3,4, Noémi Mallet1,2,3, Marin Bralo5,6,7
1Research Unit NeuroBiology of Diabetes, Helmholtz Munich, Neuherberg, Germany.
Abstract:
Deficiency of the Monocarboxylate Transporter 8 (MCT8) severely impairs thyroid hormone (TH) transport into the brain, disrupting brain development as well as peripheral TH homeostasis. Studies assessing MCT8 expression patterns and tissue-specific pathologies induced by local TH-deficiency are often inconclusive due to unreliable antibody staining and the lack of functional tools to specifically target MCT8-expressing cells. For this purpose, we generated non-inducible Mct8-Cre and tamoxifen-inducible Mct8-CreERT2 mice. Mct8-Cre;Sun1-sfGFP mice demonstrated ubiquitous Sun1-sfGFP expression, due to early recombination driven by Mct8 gene expression at the stage of trophoblast implantation. Tamoxifen injection in 6-week-old Mct8-CreERT2 mice induced reporter expression specifically in Mct8-expressing cells in the brain and peripherally in liver, kidney, and thyroid, without leaky reporter expression in vehicle controls. Using vDISCO tissue clearing and 3D-imaging of GFP-nanobody-boosted mice, we further identified the sublingual salivary gland and the prostate as prominent Mct8-expressing organs. Nuclei from Mct8-expressing cells in the brain could selectively be enriched using fluorescence-activated nuclei sorting on Mct8-CreERT2;Sun1-sfGFP mice and characterized as choroid plexus cells and tanycytes. Our new inducible Mct8-CreERT2 line provides researchers with a tool to reliably mark, enrich, and characterize Mct8-expressing cells and to genetically modify genes specifically in these cells to study thyroid hormone transport and function.
Insights
Researchers developed new Mct8-CreERT2 mice to precisely track Monocarboxylate Transporter 8 (MCT8) cells. This tool aids in studying thyroid hormone (TH) transport and brain development, overcoming previous experimental limitations.
Area of Science:
- Neuroscience
- Endocrinology
- Genetics
Background:
- Monocarboxylate Transporter 8 (MCT8) deficiency severely impacts thyroid hormone (TH) transport to the brain, hindering development and peripheral TH balance.
- Previous studies on MCT8 expression and related pathologies are limited by unreliable antibodies and lack of tools to target MCT8-expressing cells.
Purpose of the Study:
- To generate and validate novel Mct8-Cre and tamoxifen-inducible Mct8-CreERT2 mouse models.
- To provide a reliable tool for marking, enriching, and genetically manipulating MCT8-expressing cells for research.
Main Methods:
- Generation of non-inducible Mct8-Cre and inducible Mct8-CreERT2 mouse lines.
- Utilized tamoxifen induction for specific reporter gene expression in Mct8-expressing cells.
- Employed vDISCO tissue clearing, 3D-imaging, and fluorescence-activated nuclei sorting (FANS) for cell identification and enrichment.
Main Results:
- Mct8-Cre mice showed ubiquitous reporter expression due to early Mct8 gene activity.
- Mct8-CreERT2 mice exhibited specific reporter expression in brain, liver, kidney, and thyroid post-tamoxifen induction, with no leaky expression.
- Identified sublingual salivary gland and prostate as significant MCT8-expressing organs.
- Successfully enriched and characterized choroid plexus cells and tanycytes using FANS.
Conclusions:
- The inducible Mct8-CreERT2 mouse line is a valuable tool for precise targeting of MCT8-expressing cells.
- This model system enables detailed investigation of TH transport, homeostasis, and function in specific cell populations.
- Facilitates future research into MCT8-related disorders and therapeutic strategies.
