The Hippo pathway effector YAP is an essential regulator of ductal progenitor patterning in the mouse submandibular gland
Aleksander D Szymaniak,
Rongjuan Mi,
Shannon E McCarthy,
Adam C Gower,
Taylor L Reynolds,
Michael Mingueneau,
Maria Kukuruzinska,
Xaralabos Varelas
Affiliations
Aleksander D Szymaniak
Department of Biochemistry, Boston University School of Medicine, Boston, United States
Rongjuan Mi
Department of Biochemistry, Boston University School of Medicine, Boston, United States; Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, United States
Shannon E McCarthy
Department of Biochemistry, Boston University School of Medicine, Boston, United States
Adam C Gower
Clinical and Translational Science Institute, Boston University, Boston, United States
Taylor L Reynolds
Immunology Research, Biogen, Cambridge, United States
Michael Mingueneau
Immunology Research, Biogen, Cambridge, United States
Maria Kukuruzinska
Department of Molecular and Cell Biology, Boston University School of Dental Medicine, Boston, United States
Salivary glands, such as submandibular glands (SMGs), are composed of branched epithelial ductal networks that terminate in acini that together produce, transport and secrete saliva. Here, we show that the transcriptional regulator Yap, a key effector of the Hippo pathway, is required for the proper patterning and morphogenesis of SMG epithelium. Epithelial deletion of Yap in developing SMGs results in the loss of ductal structures, arising from reduced expression of the EGF family member Epiregulin, which we show is required for the expansion of Krt5/Krt14-positive ductal progenitors. We further show that epithelial deletion of the Lats1 and Lats2 genes, which encode kinases that restrict nuclear Yap localization, results in morphogenesis defects accompanied by an expansion of Krt5/Krt14-positive cells. Collectively, our data indicate that Yap-induced Epiregulin signaling promotes the identity of SMG ductal progenitors and that removal of nuclear Yap by Lats1/2-mediated signaling is critical for proper ductal maturation.