Dataset Information

APKC?-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.

ABSTRACT: Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation treatment, but it is not known if salivary stem and progenitor cells play a role. We show that radiation inactivates aPKC? and promotes nuclear redistribution of Yap in a population of label-retaining cells in the acinar compartment of the parotid gland (PG)- which comprises a heterogeneous pool of salivary progenitors. Administration of IGF-1 post-radiation maintains activation of aPKC? and partially rescues Yap's cellular localization in label retaining cells, while restoring salivary function. Finally, IGF-1 fails to restore saliva production in mice lacking aPKC?, demonstrating the importance of the kinase as a potential therapeutic target.

SUBMITTER: Chibly AM

PROVIDER: S-EPMC5910385 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature

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aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.

Chibly Alejandro M AM Wong Wen Yu WY Pier Maricela M Cheng Hongqiang H Mu Yongxin Y Chen Ju J Ghosh Sourav S Limesand Kirsten H KH

Scientific reports 20180420 1

Xerostomia and salivary hypofunction often result as a consequence of radiation therapy for head and neck cancers, which are diagnosed in roughly 60,000 individuals every year in the U.S. Due to the lack of effective treatments for radiation-induced salivary hypofunction, stem cell-based therapies have been suggested to regenerate the irradiated salivary glands. Pharmacologically, restoration of salivary gland function has been accomplished in mice by administering IGF-1 shortly after radiation ...[more]

PMID: 29679075

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Project description:Interferon regulatory factor 6 ( IRF6) acts as a tumor suppressor and controls cell differentiation in ectodermal and craniofacial tissues by regulating expression of target genes. Haploinsufficiency of IRF6 causes Van der Woude and popliteal pterygium syndrome, 2 syndromic forms of cleft lip and palate. Around 85% of patients with Van der Woude express pits on the lower lip that continuously or intermittently drain saliva, and patients with the common cleft lip and palate have a higher prevalence of dental caries and gingivitis. This study aims to identify the role of IRF6 in development of exocrine glands, specifically the major salivary glands. Our transgenic mouse model that expresses LacZ reporter under the control of the human IRF6 enhancer element showed high expression of IRF6 in major and minor salivary glands and ducts. Immunostaining data also confirmed the endogenous expression of IRF6 in the developing ductal, serous, and mucous acinar cells of salivary glands. As such, we hypothesized that Irf6 is important for proper development of salivary glands and potentially other exocrine glands. Loss of Irf6 in mice causes an increase in the proliferation level of salivary cells, disorganized branching morphogenesis, and a lack of differentiated mucous acinar cells in submandibular and sublingual glands. Expression and localization of the acinar differentiation marker MIST1 were altered in Irf6-null salivary gland and pancreas. The RNA-Seq analysis demonstrated that 168 genes are differentially expressed and confer functions associated with transmembrane transporter activity, spliceosome, and transcriptional regulation. Furthermore, expression of genes involved in the EGF pathway-that is, Ereg, Ltbp4, Matn1, Matn3, and Tpo-was decreased at embryonic day 14.5, while levels of apoptotic proteins were elevated at postnatal day 0. In conclusion, our data report a novel role of Irf6 in exocrine gland development and support a rationale for performing exocrine functional tests for patients with IRF6-damaging mutations.

Dataset Information

APKC?-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.

Publications

aPKCζ-dependent Repression of Yap is Necessary for Functional Restoration of Irradiated Salivary Glands with IGF-1.

Similar Datasets

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