Cellular and Molecular Life Sciences

, Volume 75, Issue 5, pp 905–919 | Cite as

The impact of thyroid hormone in seasonal breeding has a restricted transcriptional signature

  • Didier Lomet
  • Juliette Cognié
  • Didier Chesneau
  • Emeric Dubois
  • David Hazlerigg
  • Hugues Dardente
Original Article


Thyroid hormone (TH) directs seasonal breeding through reciprocal regulation of TH deiodinase (Dio2/Dio3) gene expression in tanycytes in the ependymal zone of the medio-basal hypothalamus (MBH). Thyrotropin secretion by the pars tuberalis (PT) is a major photoperiod-dependent upstream regulator of Dio2/Dio3 gene expression. Long days enhance thyrotropin production, which increases Dio2 expression and suppresses Dio3 expression, thereby heightening TH signaling in the MBH. Short days appear to exert the converse effect. Here, we combined endocrine profiling and transcriptomics to understand how photoperiod and TH control the ovine reproductive status through effects on hypothalamic function. Almost 3000 genes showed altered hypothalamic expression between the breeding- and non-breeding seasons, showing gene ontology enrichment for cell signaling, epigenetics and neural plasticity. In contrast, acute switching from a short (SP) to a long photoperiod (LP) affected the expression of a much smaller core of 134 LP-responsive genes, including a canonical group previously linked to photoperiodic synchronization. Reproductive switch-off at the end of the winter breeding season was completely blocked by thyroidectomy (THX), despite a very modest effect on the hypothalamic transcriptome. Only 49 genes displayed altered expression between intact and THX ewes, including less than 10% of the LP-induced gene set. Neuroanatomical mapping showed that many LP-induced genes were expressed in the PT, independently of the TH status. In contrast, TH-sensitive seasonal genes were principally expressed in the ependymal zone. These data highlight the distinctions between seasonal remodeling effects, which appear to be largely independent of TH, and TH-dependent localised effects which are permissive for transition to the non-breeding state.


Biological rhythms Circannual clock GnRH Melatonin Pars tuberalis Photoperiod Pituitary Seasonality Sheep Tanycytes Thyrotropin 



Differentially expressed genes


Folliculo-stimulating hormone


G-protein-coupled receptor


In situ hybridization


Luteinizing hormone


Long photoperiod


Medio-basal hypothalamus




Pars distalis of the pituitary




Pars tuberalis of the pituitary




Short photoperiod


Thyroid hormone






Thyrotropin-releasing hormone






Zeitgeber time



We thank the staff of the CIRE platform for assistance with surgical procedures, Damien Capo, Olivier Lasserre and Didier Dubreuil from the Unité Expérimentale PAO no. 1297 (EU0028) for taking care of the animals and blood sampling, staff of the IGF sequencing platform (Montpellier, France) and Shona Wood (Manchester University, UK) for help with bioinformatics.


This work was supported by a Career Integration Grant (No. 320553) from the FP7-Marie-Curie actions (H.D.).

Author contributions

DL, DC & HD carried out the molecular lab work; JC carried out surgeries; ED performed the RNAseq experiments; HD designed the study, performed data analysis and drafted the manuscript; DH contributed intellectual support and helped draft the manuscript. All authors gave final approval for publication.

Compliance with ethical standards

Conflict of interest

The authors have no conflict of interest.

Ethical approval

All experimental procedures were performed in accordance with international (directive 2010/63/UE) and national legislation (décret no. 2013–118) governing the ethical use of animals in research (authorization no. E37–175-2 and no. A38 801). All procedures used in this work were evaluated by a local ethics committee (Comité d’Ethique en Expérimentation Animale Val de Loire) and approved by the Ministry of Higher Education and Research (Project No. 00710.02).

Supplementary material

18_2017_2667_MOESM1_ESM.pdf (232 kb)
Suppl. Fig.S1(associated to Fig. 1): Transcriptomics of the non-breeding to breeding transition (Experiment 1). (A) Procedure for dissecting the MBH block. The two pictures on the left are ventral views of the ovine brain; the two pictures on the right are coronal slices. Details and abbreviations are provided in the panel. (B) Procedure for the RNAseq analysis. First, RNA were individually extracted from each MBH block resulting in 18 samples: 6 RNA samples for each of the 3 groups (May, Aug & Nov). Then, for each of the 3 groups, RNA were randomly pooled in 2 equimolar mixes from 3 animals. This resulted in 6 cDNA libraries, which were sequenced and submitted to alignment and statistical analysis as indicated. (C) Normalized RNAseq counts for genes analyzed by qPCR in Fig. 1D. Note the broad correlation between the two datasets. Slc7a8 was absent from this genome assembly (Oar3.1). Suppl. Fig.S2 (associated to Fig. 2): Impact of TH on transcriptomics of the breeding to non-breeding transition (Experiment 2). (A) Validation of the THX procedure using RIA for TSH and T4 in intact ewes (pilot Experiment for Experiment 2). The upper panel shows temporal profiles for both hormones 1.5 month prior to surgery and 2.5 months after surgery. The red dotted line corresponds to the limit of the T4 assay sensitivity (4.7 ng/ml). The histogram (lower panel) shows mean ± sem for the two periods. (B) Characterization of the hypothyroid state by qRT-PCR analysis of select genes within the pars distalis (PD) of the pituitary. The picture on the left indicates that the caudalmost part of the PD was used. Note the > 175-fold increase in Tshb, the 50-70% decreases in Dio2 and Hr. Also note that relative levels of Lhb and Fshb are not impacted by photoperiod or THX. (C) Hormonal profiling of the response in plasma levels for PRL. Neither photoperiod nor treatment had any statistically significant impact (data not shown). The orange line indicates photoperiod. (D) Procedure for the RNAseq analysis. First, RNA were individually extracted from each MBH block resulting in 24 samples: 8 RNA samples for each of the 3 groups (SP, LP & LP-THX). Then, for each of the 3 groups, RNA were randomly pooled in 2 equimolar mixes from 4 animals. This results in 6 cDNA libraries, which are sequenced and submitted to alignment and statistical analysis as indicated. (E) qRT-PCR analysis of Hr, Slc16a2, Kiss1 and Npvf in the MBH. Suppl Fig.S3 (associated to Fig. 3): Investigating the time-specific role of TH on the photoperiodic transcriptional network of the MBH (Experiment 3). Non-breeding to breeding transition: (A) Hormonal profiling of the seasonal response in plasma levels for PRL (left) and TSH (right) following THX. The orange line indicates photoperiod. Breeding to non-breeding transition: (B) Analysis of individual TSH mean levels during the 7 weeks before (i.e. 14 samples) and 7 weeks after (i.e. 14 samples) shearing in Sham-operated and THX ewes (left and right panels, respectively). TSH levels were significantly decreased after shearing in THX animals while they were significantly - albeit modestly, check the y-axis - increased in Sham ewes (pairwise t-test comparison). (C) Mean weight of ewes in the experimental group sham-operated or THX before the transition to breeding. Two-way ANOVA reveals a trend towards lower weight in THX animals at the end of experiment. (D) Hormonal profiling of the seasonal response in plasma levels for PRL following THX before the transition to non-breeding. The dotted line indicates time of shearing; the orange line indicates photoperiod. (E) Characterization of the hypothyroid state by qRT-PCR analysis of select genes within the pars distalis (PD) of the pituitary. The picture on the left indicates that the caudalmost part of the PD was used. Note the > 40-fold increase in Tshb, the 50-70% decreases in Dio2 and Hr. Also note that relative levels of Lhb and Fshb are not impacted by THX (PDF 231 kb)
18_2017_2667_MOESM2_ESM.docx (24 kb)
Suppl.Table S1: This folder includes 3 sheets. (i) List of qRT-PCR primers and size of the PCR amplicons (Fig. 1D, Fig. 2B, Fig. 2D & Fig. 2E). (ii) List of probes used for ISH (Fig. 3D & Fig.S4). (iii) Results of the two-way ANOVA for ISH data of Fig. 3D (DOCX 24 kb)
18_2017_2667_MOESM3_ESM.xlsx (1015 kb)
Suppl.Table S2: RNAseq data and pathway analysis for the non-breeding to breeding transition (associated with Fig. 1). Folder includes 12 sheets: (i) M vs A: DEG using EdgeR. (ii) M vs A: DEG using DESeq2. (iii) A vs N: DEG using EdgeR. (iv) A vs N: DEG using DESeq2. (v) M vs N: DEG using EdgeR. (vi) M vs N: DEG using DESeq2. (vii) up-regulated pathways and GO terms (Cpdb analysis): M/A comparison. (viii) down-regulated pathways and GO terms (Cpdb analysis): M/Acomparison. (ix) up-regulated pathways and GO terms (Cpdb analysis): A/N comparison. (x) down-regulated pathways and GO terms (Cpdb analysis): A/N comparison. (xi) up-regulated pathways and GO terms (Cpdb analysis): M/N comparison. (xii) down-regulated pathways and GO terms (Cpdb analysis): M/N comparison (XLSX 1014 kb)
18_2017_2667_MOESM4_ESM.xlsx (6.1 mb)
Suppl.Table S3: RNAseq data and pathway analysis for the breeding to non-breeding transition / long day exposure (associated with Fig. 2). Folder includes 4 sheets: (i) LP vs SP: list of DEG using EdgeR. (ii) LP vs SP: list of DEG using DESeq2, p value < 0.05. (iii) LP vs LP-THX: list of DEG using EdgeR. (iv) LP vs LP-THX: list of DEG using DESeq2, pVal < 0.05 (XLSX 6282 kb)


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Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  1. 1.PRC, INRA, CNRS, IFCE, Université de ToursNouzillyFrance
  2. 2.MGX-Montpellier GenomiX, Institut de Génomique FonctionnelleMontpellierFrance
  3. 3.Department of Arctic and Marine BiologyUniversity of TromsøTromsøNorway

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