The Hippo pathway effector YAP is an essential regulator of ductal progenitor patterning in the mouse submandibular gland
- Boston University School of Medicine, United States
- Biogen, United States
- Boston University School of Dental Medicine, United States
Abstract
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.
Data availability
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The Hippo pathway effector YAP is an essential regulator of submandibular gland ductal progenitor patterningPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE90480).
Article and author information
Author details
Funding
March of Dimes Foundation (1-FY14-219)
- Xaralabos Varelas
National Heart, Lung, and Blood Institute (R01 HL124392)
- Xaralabos Varelas
Sjogren's Syndrome Foundation (Research Grant)
- Xaralabos Varelas
National Institute of Dental and Craniofacial Research (R21 DE024954)
- Maria Kukuruzinska
National Center for Advancing Translational Sciences (UL1-TR001430)
- Adam C Gower
- Xaralabos Varelas
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health.Animal care and handling was consistent with the recommendations of the Panel on Euthanasia of the American Veterinary Medical Association. Prior to the initiation of experiments, all study protocols were reviewed and modified according to the suggestions of the Boston University School of Medicine IACUC. The Boston University School of Medicine animal management program is accredited by the American Association for the Accreditation of Laboratory Animal Care, and meets National Institutes of Health standards as set forth in the Guide for the Care and Use of Laboratory Animals (DHHS Pub.No. (NIH) 85-23, rev 1985). Boston University's Animal Welfare Assurance number is A-3316-01.
Copyright
© 2017, Szymaniak et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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The Hippo pathway effector YAP is an essential regulator of ductal progenitor patterning in the mouse submandibular gland
eLife 6:e23499.
https://doi.org/10.7554/eLife.23499
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