Identification of Gallbladder‐Specific Distal Regulatory Sequence of Murine Sox17

ABSTRACT Sox17 is a key transcriptional regulator of endoderm formation and function in the gallbladder, blood vessels and reproductive organs. Although multiple transcript variants of Sox17 have been suggested, the precise mechanisms underlying their time‐ and tissue‐specific expression remain unclear. In this study, we discovered two putative regulatory sequences (R1 and R2) adjacent to different transcription start sites of mouse Sox17 exon 1 and generated deletion mice for these regions (Sox17Δdr/Δdr). Sox17Δdr/Δdr mice were alive and fertile, and they possessed a normal‐sized gallbladder. However, semiquantitative analysis of immunostaining showed that the expression levels of SOX17 in Sox17Δdr/Δdr embryos were reduced to less than 50% of the wild‐type in the gallbladder epithelium. Furthermore, the bile ductal epithelium marker SOX9 was abnormally upregulated, and PAS/DBA‐positive mucin secretion‐like epithelial cells were induced in the Sox17Δdr/Δdr gallbladder. Our results demonstrate that the distal sequence of Sox17, including R1 and R2, is important for the regulation of Sox17 gene expression in the embryonic gallbladder and is crucial for normal gallbladder epithelial development. Sox17 regulates embryogenesis and tissue homeostasis, but the mechanisms of its specific expression remain unclear. In Sox17Δdr/Δdr mice, which lack a distal sequence with two putative regulatory regions, SOX17 expression is reduced in the gallbladder, with epithelial differentiation defects, highlighting the distal sequence's role in gallbladder development.