Endocrine Abstracts

Background: Previously, we identified a novel gene, BOREALIN/CDCA8 in congenital hypothyroidism. Patients with BOREALIN mutations had thyroid dysgenesis, from asymmetric lobes to athyreosis (Carré et al. Hum Mol Genet 2017). Borealin is a major component of the Chromosomal Passenger Complex, an essential regulator of mitosis. We demonstrated a new feature of BOREALIN: involvement in the adhesion and the migration of the thyrocytes.

Objective: Further understand the role of Borealin in thyroid development and function.

Methods: Borealin+/- mice were studied during development, at 4 and 18 months. Borealin-/- mice were not available because they die at E5.5. We documented thyroid morphology, performed immunohistology with thyroid markers (Nkx2-1, Thyroglobulin, T4) and we analyzed the thyroid function. We used a well-established model with antithyroid drug induced hypothyroidism which was applied to the Borealin+/- and wild-type mice.

Results: First of all, Borealin+/- mice did not develop hypothyroidism at the adult stage (4-month-old) but they were significantly more sensitive to antithyroid drugs with a more profound hypothyroidism (T4: 41% less for Borealin+/- vs wild-type, P<0.01). Four months-old Borealin +/- thyroids were significantly more hyperplastic with larger follicles surfaces in comparison with wild-type thyroids (P<0.05). Thus, the Borealin+/- mice remain euthyroid at the expense of developing goiters. For elder mice, thyroid morphology of Borealin+/- was altered with heterogeneity in size of follicles with predominantly very large follicles and thyroids significantly more hyperplastic compared with wild-type (0,34 mg/g thyroid weight/animal weight vs 0,23 mg/g, P<0.05). We found that thyroids of Borealin+/- were significantly hyperplastic at E9.5 in comparison with wild-type, and hypoplastic from E11.5 to E17.5 (P<0.05). Thyroid development thus was abnormal in Borealin+/- compared to wild-type. In addition, transcriptome analysis of thyroids were performed at different stages. Specific pathways were disturbed in Borealin+/- thyroids at E13.5, at 4 and 18 months, mainly adhesion and motility pathways. At 18 months, Borealin+/- thyroid are enriched in cytoskeleton, cell cycle and thyroid cancer gene sets compared to wild-type.

Conclusion: Borealin is involved in crucial steps of the thyroid lifetime cycle. These data demonstrate the involvement of Borealin in the structural organization of the thyroid gland and consolidate the role of Borealin in thyroid development and function, which supports its involvement in thyroid dysgenesis of patients with congenital hypothyroidism. Impaired Borealin function plays also a role in morphologic deregulation in thyroids along time.