Runx1 mediates the development of the granular convoluted tubules in the submandibular glands

Abstract

The mouse granular convoluted tubules (GCTs), which are only located in the submandibular gland (SMG) are known to develop and maintain their structure in an androgen-dependent manner. We previously demonstrated that the GCTs are involuted by the epithelial deletion of core binding factor β (CBFβ), a transcription factor that physically interacts with any of the Runt-related transcription factor (RUNX) proteins (RUNX1, 2 and 3). This result clearly demonstrates that the Runx /Cbfb signaling pathway is indispensable in the development of the GCTs. However, it is not clear which of the RUNX proteins plays useful role in the development of the GCTs by activating the Runx /Cbfb signaling pathway. Past studies have revealed that the Runx /Cbfb signaling pathway plays important roles in various aspects of development and homeostatic events. Moreover, the Runx genes have different temporospatial requirements depending on the biological situation. In the present study, the GCTs of the SMG showed a remarkable phenotype of, which phenocopied the epithelial deletion of Cbfb, in epithelial-specific Runx1 conditional knock-out (cKO) mice. The results indicate that Runx1 works as a partner of Cbfb during the development of the GCTs. We also discovered that the depletion of Runx1 resulted in the reduced secretion of saliva in male mice. Consistent with this finding, one of the water channels, Aquaporin-5 (AQP5) was mislocalized in the cytoplasm of the Runx1 mutants, suggesting a novel role of Runx1 in the membrane trafficking of AQP5. In summary, the present findings demonstrated that RUNX1 is essential for the development of the GCTs. Furthermore, RUNX1 could also be involved in the membrane trafficking of the AQP5 protein of the acinar cells in the SMG in order to allow for the proper secretion of saliva.

Runx1-Stat3 signaling regulates the epithelial stem cells in continuously growing incisors

“…To analyze the functional role of Runx1 in the dental epithelium of the growing incisors, we examined the incisal phenotypes of conditional knockout ( K14-Cre/Runx1 fl/fl ) mice, in which Runx1 expression was disrupted in the epithelium using Cre recombination 26 . The efficiency of the K14-Cre recombination of our mice was previously confirmed using Rosa26R reporter mice and X-gal staining 9 .…”

“…C57/BL6 mice were used as wild-type (WT) mice. Mice expressing Cre recombinase under the control of keratin 14 promoter (K14-Cre; strain Tg(KRT14-cre)1Amc) were bred with floxed Runx1 mice (Runx1tm3Spe) to produce epithelium-specific Runx1 -knockout ( K14-Cre/Runx1 fl/fl ) mice, as described previously 9 , 26 . We used their littermates or knockout embryos that did not carry the K14-Cre/Runx1 fl/fl genotype as controls.…”

Transcriptional profiling reveals gland-specific differential expression in the three major salivary glands of the adult mouse

“…However, the regulation of salivary gland development by transcription factors has focused on the mouse SMG model, with little attention paid to other mammalian species or salivary glands. Examples of the transcription factors thought to be important in the development of the mouse SMG include Runx1, Six1, and Sox9 (5,27,38). Other transcription factors, like SMARCA2, FOXA1, and SOX10 (15,17,19,37), have been proposed as biomarkers for different types of human salivary gland tumors, while Ascl2 and RORc (13,22) have been implicated in Sjögren's syndrome.…”

Physiology, Pathology and Regeneration of Salivary Glands

“…A relevant sexual dimorphism appears in mice: SMG glands differ significantly between male and female mice, in particular the granular convoluted tubules (GCT), which are larger and more numerous in the male organs. Such a dimorphism has been lost in humans, and GCTs are absent in human SMGs, independently of gender [8]. Murine submandibular glands specifically synthetize EGF and NGF in the GCTs following testosterone activity, while their production in humans occurs in the striated ducts.…”