Background: BOREALIN/CDCA8 mutations are associated with congenital hypothyroidism and thyroid dysgenesis. Borealin is involved in mitosis as part of the Chromosomal Passenger Complex. Although BOREALIN mutations decrease thyrocyte adhesion and migration, little is known about the specific role of Borealin in the thyroid. Methods: We characterized thyroid development and function in Borealin-deficient (Borealin +/-) mice using histology, transcriptomic analysis, and quantitative PCR. Results: Thyroid development was impaired with a hyperplastic anlage on embryonic day E9.5 followed by thyroid hypoplasia from E11.5 onward. Adult Borealin +/- mice exhibited euthyroid goiter and defect in thyroid hormone synthesis. Borealin +/- aged mice had disorganized follicles and papillary-like structures in thyroids due to ERK pathway activation and a strong increase of Braf-like genes described by The Cancer Genome Atlas (TCGA) network of papillary thyroid carcinoma. Moreover, Borealin +/- thyroids exhibited structural and transcriptomic similarities with papillary thyroid carcinoma tissue from a human patient harboring a BOREALIN mutation, suggesting a role in thyroid tumor susceptibility. Conclusion: These findings demonstrate Borealin involvement in critical steps of thyroid structural development and function throughout life. They support a role for Borealin in thyroid dysgenesis with congenital hypothyroidism. Close monitoring for thyroid cancer seems warranted in patients carrying BOREALIN mutations.
Congenital Hypothyroidism , Thyroid Dysgenesis , Thyroid Neoplasms , Animals , Mice , Cell Cycle Proteins/genetics , Congenital Hypothyroidism/genetics , Thyroid Cancer, Papillary/genetics , Thyroid Dysgenesis/genetics , Thyroid Neoplasms/genetics
Recently, DCC (Deleted in Colorectal Cancer) protein has been forwarded as a receptor for netrin. The Netrin/DCC complex is critical for axon guidance and cell migration. In the developing nervous system, netrin protein secreted by midline cells attracts commissural axons by activating the DCC receptor on growth cones. This attraction can be switched to repulsion or silenced completely, depending on the DCC binding partner. The potential suppressor function of DCC in prostate tumorigenesis, through a still unknown mechanism, prompted us to quantify the expression of several genes involved in this axon guidance pathway. The relative expression levels of DCC, NEO1, NTN1, NTN2L, NTN4, UNC5C, Slit1, Slit2, Slit3, Robo1 and Robo2 were simultaneous quantified in 48 tumors and 7 normal prostate tissues by using real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR). A reduction in DCC, NEO1, NTN1 and NTN4 expression was observed in prostate tumors, while many of the same prostate tumors over-expressed either Slit genes or their receptors, Robo.
Adenocarcinoma/genetics , Biomarkers, Tumor/genetics , Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Adenocarcinoma/metabolism , Adenocarcinoma/secondary , Axons , Biomarkers, Tumor/metabolism , Cell Adhesion Molecules/genetics , Cell Adhesion Molecules/metabolism , DCC Receptor , DNA Primers/chemistry , Humans , Intercellular Signaling Peptides and Proteins , Male , Membrane Proteins/genetics , Membrane Proteins/metabolism , Neoplasm Proteins/metabolism , Neoplasm Staging , Nerve Growth Factors/genetics , Nerve Growth Factors/metabolism , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Netrin-1 , Netrins , Prostatic Neoplasms/metabolism , Prostatic Neoplasms/pathology , RNA, Messenger/metabolism , Receptors, Cell Surface , Receptors, Immunologic/genetics , Receptors, Immunologic/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Roundabout Proteins
