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

Salivary gland stem cells: A review of development, regeneration and cancer

“…YAP, a negative regulator of the HIPPO pathway involved in organ size and cell proliferation (Wu et al , 2003), is enriched in the nucleus of KRT14+ cells in the ducts during early stages of SG development (E13.5). Ablation of Yap , and thus activation of the HIPPO pathway, in KRT5+/KRT14+ cells before SG initiation reduces the production of Epiregulin, an ErbB receptor ligand which is involved in cell fate control (Gregorieff et al , 2015) and is required for KRT5+/KRT14+ cell expansion, thereby perturbing epithelial branching and duct formation (Szymaniak et al , 2017). In addition, restriction of nuclear Yap localization, via deletion of Lats1 and Lats2 , results in the expansion of KRT5+/KRT14+ cells, aberrant enlargement of ducts and reduced end bud formation, further illustrating the requirement of controlled YAP signaling during lineage formation and epithelial morphogenesis in the developing SG (Szymaniak et al , 2017).…”

“…YAP, a negative regulator of the HIPPO pathway involved in organ size and cell proliferation (Wu, Huang, Dong, & Pan, 2003), is enriched in the nucleus of KRT141 cells in the ducts during early stages of SG development (E13.5). Ablation of Yap, and thus activation of the HIPPO pathway, in KRT51/KRT141 cells before SG initiation reduces the production of Epiregulin, an ErbB receptor ligand which is involved in cell fate control (Gregorieff, Liu, Inanlou, Khomchuk, & Wrana, 2015) and is required for KRT51/KRT141 cell expansion, thereby perturbing epithelial branching and duct formation (Szymaniak et al, 2017) (Wright et al, 2015) and similarly, blocking RA signaling in isolated epithelia with the pan-RAR antagonist BMS 493 results in reduced branching morphogenesis (Wright et al, 2015) and repressed cell proliferation (Abashev, Metzler, Wright, & Sandell, 2017 (Figure 3), it remains unclear if cells that co-express KRT5 and 14 or those that solely express one but not the other keratin continue to contribute to the different epithelial lineages.…”

Integrin‐FAK‐CDC42‐PP1A signaling gnaws at YAP/TAZ activity to control incisor stem cells

“…Analyses of YAP/TAZ activity in a variety of tissues have demonstrated common and differing roles for YAP and TAZ in stem/progenitor cell expansion in development and regeneration. Conditional deletion studies of YAP/TAZ in developing and adult animals have shown the depletion of stem/ progenitor cell populations in several organs [39], including the lung [34,40], salivary gland [41], pancreas [42,43], epidermis [44,45], and, most recently, the incisors, as demonstrated by Hu et al [1]. The potency of YAP/TAZ for establishing and maintaining lineage specific stem cells has been further demonstrated by the ability of transient YAP or TAZ expression to reprogram differentiated mammary, neural, and pancreatic cells into local tissue specific stem cells with self-renewal and differentiation capacity [46].…”

Specific complexes derived from extracellular matrix facilitate generation of structural and drug‐responsive human salivary gland microtissues through maintenance stem cell homeostasis

“…To further investigate the effect of s-Ecx on stem cell maintenance and determine the characteristics of these duct-like structures, we next evaluated the expression levels of SG duct and acinus marker genes involving in the development and mature stage. The expression of K19, a progenitor duct-cell marker (Szymaniak et al, 2017), was reduced when cultured without s-Ecx (Figure 4b-c and e). Immunohistochemistry staining further showed that K19 was almost expressed around the duct-like structures.…”