SLC26A2-mediated sulfate metabolism is essential for the tooth development

Yoshida, Y.; Inubushi, T.; Yokoyama, M.; Nag, P.; Oka, A.; Murotani, T.; Kani, R.; Shiraishi, Y.; Kurosaka, H.; Takahata, Y.; Nishimura, R.; Papagerakis, P.; Yamashiro, T.

doi:10.1101/2023.03.30.534919

bioRxiv · 10.1101/2023.03.30.534919

SLC26A2-mediated sulfate metabolism is essential for the tooth development

Yoshida, Y.·Inubushi, T.·Yokoyama, M.·Nag, P.·Oka, A.·Murotani, T.·Kani, R.·Shiraishi, Y.·Kurosaka, H.·Takahata, Y.·Nishimura, R.·Papagerakis, P.·Yamashiro, T.

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Abstract

The sulfate transporter gene SLC26A2 is responsible for diastrophic dysplasia, which represents skeletal dysplasia in humans. This highlights the importance of sulfate metabolism in skeletal formation. SLC26A2-related chondrodysplasia is also known to exhibit abnormalities in craniofacial and tooth development. Although the function of SLC26A2 in mammals has been investigated using genetic mouse models, the essential role of SLC26A2 during craniofacial and tooth development has not been elucidated. In this study, we demonstrate the pivotal roles of SLC26A2-mediated sulfate metabolism during tooth development. Analysis of Slc26a2 expression reveals that it is predominantly expressed in dental tissues, including odontoblasts and ameloblasts, during tooth development. Slc26a2 knockout mice (Slc26a2-KO-{Delta}exon2) exhibit a retrognathic upper jaw, small upper incisors, and hypoplasia of upper molars. Additionally, upper incisors and molars in Slc26a2-KO-{Delta}exon2 mice display flattened odontoblasts and nuclei that lack intracellular polarity. In contrast, tooth phenotype is not remarkable in lower incisors and molars. Furthermore, the expression of odontoblast differentiation markers, Dspp and Dmp1, is significantly decreased in the upper molars of Slc26a2-deficient mice. Ex vivo organ culture of tooth germs by implantation of Slc26a2-deficient tooth germs under the kidney capsule reveals hypoplasia of the dentin matrix as well as tooth root shortening. In vitro studies using human dental pulp stem cells (hDPSCs) show that the expression levels of Dspp and Dmp1 in shSlc26a2 knockdown cells are significantly decreased compared to control cells. Collectively, our data demonstrate that SLC26A2-mediated sulfate metabolism is essential for tooth development. This study may provide insight into the mechanisms underlying tooth abnormalities in patients with recessively inherited chondrodysplasias caused by mutations in the SLC26A2 gene.

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Yoshida, Y., Inubushi, T., Yokoyama, M., Nag, P., Oka, A., Murotani, T., Kani, R., Shiraishi, Y., Kurosaka, H., Takahata, Y., Nishimura, R., Papagerakis, P., Yamashiro, T.. 2023-04-02. SLC26A2-mediated sulfate metabolism is essential for the tooth development. https://doi.org/10.1101/2023.03.30.534919

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