Understanding Pathologies Associated With Deficient LATS1/2 Kinase in Salivary Glands

Objectives: The salivary gland epithelium lines a complex network of branched ductal tubes that end in acini, which together produce, transport and secrete saliva. The development and homeostasis of the salivary epithelium requires the precise coordination of a multitude of signals, many of which are poorly understood. Our prior studies have indicated that the nuclear activity of the transcriptional regulator Yap, a key effector of the Hippo pathway, is critical for the patterning of Krt5/Krt14-positive progenitors in the developing submandibular gland (SMG). Further, exclusion of Yap from the nucleus, which is mediated by the Lats1 and Lats2 (Lats1/2) kinases, is essential for the developmental maturation of the ductal epithelium. We therefore hypothesized that the Lats1/2 kinases play a critical role in the homeostasis of the adult salivary gland. To test this, we conditionally deleted Lats1/2 in mature luminal epithelial cells in mouse SMG ducts.
Methods: Conditional deletion of the Lats1/2 genes was achieved by crossing Krt8-CreERT2 mice with Lats1/2 loxP/loxP mice. Lats1/2 knockout was achieved in 12-week-old female mice following tamoxifen treatment. Paraffin-embedded sections of Lats1/2 deleted (Lats1/2-cnull) SMGs were compared to age- and sex-matched tamoxifen-treated controls (CON) using immunohistochemistry analyses.
Results: Lats1/2-deleted SMGs exhibited prominent morphological alterations with an apparent loss of acinar morphology, disorganized ductal structures, and stromal disorganization. Increases in proliferative Ki67+ ductal epithelial cells were also observed, along with an interstitial accumulation of CD45+ lymphocytes.
Conclusions: SMGs of Lats1/2-cnull mice exhibited abnormal morphology resembling diseased salivary gland epithelium, including features similar to those found in Sjogren’s Syndrome. Further analysis of the Lats1/2-deleted mouse model will guide a better understanding of salivary gland pathologies, which will hopefully offer new opportunities for development of early diagnosis or targeted treatment interventions.