NFIB Regulates Embryonic Development of Submandibular Glands

Abstract

NFIB (nuclear factor I B) is a NFI transcription factor family member, which is essential for the development of a variety of organ systems. Salivary gland development occurs through several stages, including prebud, bud, pseudoglandular, canalicular, and terminal. Although many studies have been done to understand mouse submandibular gland (SMG) branching morphogenesis, little is known about SMG cell differentiation during the terminal stages. The goal of this study was to determine the role of NFIB during SMG development. We analyzed SMGs from wild-type and Nfib-deficient mice (Nfib (-/-)). At embryonic (E) day 18.5, SMGs from wild-type mice showed duct branching morphogenesis and differentiation of tubule ductal cells into tubule secretory cells. In contrast, SMGs from Nfib (-/-) mice at E18.5 failed to differentiate into tubule secretory cells while branching morphogenesis was unaffected. SMGs from wild-type mice at E16.5 displayed well-organized cuboidal inner terminal tubule cells. However, SMGs from Nfib (-/-) at E16.5 displayed disorganized inner terminal tubule cells. SMGs from wild-type mice at E18.5 became fully differentiated, as indicated by a high degree of apicobasal polarization (i.e., presence of apical ZO-1 and basolateral E-cadherin) and columnar shape. Furthermore, SMGs from wild-type mice at E18.5 expressed the protein SMGC, a marker for tubule secretory cells. However, SMGs from Nfib (-/-) mice at E18.5 showed apicobasal polarity, but they were disorganized and lost the ability to secrete SMGC. These findings indicate that the transcription factor NFIB is not required for branching morphogenesis but plays a key role in tubule cell differentiation during mouse SMG development.

Adenoid cystic carcinomas of the salivary gland, lacrimal gland, and breast are morphologically and genetically similar but have distinct microRNA expression profiles

“…3 and 5). The function of NFIB is poorly characterized but is crucial for salivary gland embryonic development and paradoxically serves as a metastatic driver in some cancers while having a tumor suppressor function others [59][60][61][62][63]. It is interesting that the salivary gland and breast are the two tissues in which NFIB is expressed in the highest level among a large selection of human tissues in the Genotype-Tissue Expression project (GTEx) ( Figure S3) [64].…”

The convergent roles of the nuclear factor I transcription factors in development and cancer

“…Although the role of NFIB in salivary gland development has not been well studied, Nfib knockout mice display defects in terminal tubule formation and tubule cell differentiation during submandibular gland development [83]. Given that AdCC arises from epithelial cells of the secretory glands, most commonly the salivary glands of the head and neck [84], understanding the role of NFIB in salivary gland development could contribute to our understanding of how its loss is involved in AdCC.…”

Generation of functional salivary gland tissue from human submandibular gland stem/progenitor cells

“…As in development of the mouse salivary gland, coordination of FGF and Wnt signaling regulates epithelial branching and salivary gland lumen formation, and vasoactive intestinal peptides induce the formation of a contiguous lumen [34,35]. Moreover, not only nuclear factor IB is involved in, but also SOX2 regulates acinar cell development in the mouse salivary gland [36,37]. The abundant mechanisms could be applied to the maturity of salivary gland organoids from human salivary gland stem cells in vitro and further confirmed in such human-resource modeling.…”