The Hippo pathway effector YAP is an essential regulator of ductal progenitor patterning in the mouse submandibular gland

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.

DOI: http://dx.doi.org/10.7554/eLife.23499.001

eLife digest

Our mouths are continually bathed by saliva – a thick, clear liquid that helps us to swallow and digest our food and protects us against infections. Saliva is produced by and released from salivary glands, which are organs that contain a branched network of tubes. Salivary glands can only properly develop if immature cells known as stem cells, which give rise to the mature cells in the organ, are controlled. Despite their importance for development of salivary glands, little has been known about the signals that control these stem cells.

Szymaniak et al. have now discovered new regulators of the salivary gland stem cells in mice, including essential roles in the regulation of these cells by a protein known as Yap. The Yap protein is controlled by a set of proteins that together are known as the Hippo pathway. Szymaniak et al. found that when the gene for Yap was deleted in mice very few stem cells were made, and the transport tubes of the salivary tubes failed to develop. Conversely, when the Hippo pathway was disrupted in mice there were too many stem cells because they could not properly develop into the mature cells, leading to incorrect transport tube development..

These results indicate that Yap is essential for controlling the stem cells of the salivary glands, and offer important insight into the signals that control how the salivary glands develop. The next step will be to investigate whether the Hippo pathway or Yap are affected in diseases of the salivary gland, which often show incorrect numbers of stem cells.

DOI: http://dx.doi.org/10.7554/eLife.23499.002