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COMPARATIVE ANATOMY AND MOLECULAR MECHANISMS INVOLVED IN RODENT SALIVARY GLAND DEVELOPMENT.

Byline: BANO S. and GHAFOOR S.

INTRODUCTION

Saliva which is major secretion in the oral cavity of most vertebrates is produced by three pairs of major salivary glands (parotid, submandibular, sublingual) and approximately 600-1000 minor salivary glands located within labial, buccal, lingual mucosa. A pair of parotid glands lies at back of mouth in between upper and lower jaw over ramus of mandible in relation to the masseter muscle.1 Its duct called the Stensen's duct, arises from the anterior border of the gland and opens into the oral vestibule just opposite maxillary second molar.2 Two submandibular glands (SMG) are located in the posterior part of floor of mouth within the submandibular triangle.1 Their duct is known as Wharton's duct which opens beneath the tongue lateral to lingual frenum. Two sublingual glands (SLG) lie beneath the mucous membrane in the anterior part of floor of mouth under the tongue.

It has a series of small ducts (8-20)2 known as ducts of Rivinus opening along sublingual folds and a large duct known as Bartholin's duct opening along with submandibular duct.3,4

COMPARATIVE ANATOMY OF HUMANS AND RODENT SALIVARY GLANDS

Although salivary glands of rodents and humans exhibit certain similarities, butvary to some extent in their structure, location and development. The comparisons of both are as given as follows:

1. In human beings, the parotid gland is the largest salivary gland followed by the submandibular and sublingual salivary glands while in rats submandibular salivary gland is the largest salivary gland followed by parotid and sublingual salivary glands.5

2. Human submandibular salivary gland lies inferior to mylohyoid muscle while rat submandibular gland lies on anterior side of neck having submandibular lymph nodes on one side and sternum on the other side. Sublingual gland is situated on the lateral surface of submandibular gland and both the glands are enclosed by same sheath of cervical fascia.6

3. Both human and rat ductal system consists of intercalated, striated and excretory ducts. But rats have an additional duct called granular convoluted tubule (GCT) which is an extension of striated duct, present distal to it7 and lies between striated and intercalated ducts.1,6 These are more prominent in rat submandibular glands. They can also be induced in rat parotid glands after treatment with thyroid hormone.7

4. The acinar cells of both human and rat parotid glands are purely serous and secrete saliva having a watery consistency. While human submandibular salivary gland is a mixed gland with both serous and mucous acini having serous demilunes1, rodent submandibular gland is a serous gland (Fig. 1). The intercalated and striated ducts are well-developed in both species in both glands. The sublingual gland of both species is again a mixed gland having both the serous and mucous acinar cells6 (Fig. 2).

MOLECULAR ASPECTS OF SALIVARY GLAND DEVELOPMENT

The rodent submandibular gland is an excellent model to study stages of salivary gland development as their structure, function and developmental stages are much similar to that of human beings. The embryonic development of submandibular salivary glands of mouse begins at embryonic day 11 (E 11).9 The oral epithelium is separated by the underlying neural crest cell-derived mesenchyme (ectomesenchyme) by a sheet of extracellular matrix.10 It is reported that development and maintenance of salivary glands is dependent upon reciprocal coordination between epithelium and mesenchymal interactions.11

Prenatal Development of Salivary Glands Development of salivary glands can be best described by dividing the developmental stages into pre-bud, initial bud, pseudo-glandular, canalicular and terminal bud stage1 as shown in Figure 3.

Development of salivary glands initiates as thickening of oral epithelium during pre-bud stage of Salivary gland development. During this stage, fibroblast growth factor-10 (FGF10) which is located in the mesenchyme, signals for the formation of initial bud. In homozygous mutants of FGF and its receptor fibroblast growth factor receptor-2 (FGFR2), the development arrests at this stage with no gland formation.12 In addition to FGF, another signaling molecule, Pitx2 plays the same role indirectly. It acts synergistically to increase the effect of FGF and antagonizes the function of Bone Morphogenetic Protein (BMP) which in return antagonizes FGF.1 Platelet-derived growth factor (PDGF) is also important as it induces the expression of FGF to promote epithelial proliferation.13 Sonic hedgehog (Shh) promotes the formation of initial bud. FGF signaling is important in early stages and it represses the expression of Wnts.

Wnt signaling leads salivary gland development towards maturation and hence its expression is increased when salivary gland development is at the lumenization stage.14

Around E12, epithelial thickening protrudes downwards into the underlying mesenchyme12 forming an initial bud and hence forms the initial bud stage. Ectodysplasin (Eda) is expressed in mesenchyme and its receptor Ectodysplasin-A receptor (Edar) is expressed in the epithelium. At E13.5, clefts start to appear in the buds which divide it into multiple buds. It gives a glandular appearance known as pseudo-glandular stage.1

Salivary glands undergo process of branching morphogenesis during their development similar to that seen in other organs such as lungs, kidneys and mammary glands.14,15 Salivary gland bud continues to branch and many new buds are formed which gives it an overall appearance like bunch of grapes. Branching morphogenesis increases the surface area and this increased surface area is mandatory for producing sufficient amounts of saliva.12 Branching morphogenesis starts with formation of cleft in the initial bud. Actin accumulates at the cleft site and causes cells to contract and further buds are formed.15 Many growth factors and extracellular matrix components regulate this process of branching morphogenesis likeepidermal growth factor receptor (EGFR) and FGFR.16

The epidermal growth factor receptor (EGFR) and its ligand; epidermal growth factor (EGF) and transforming growth factor-alpha (TGF-[alpha]) are present in the ductal epithelial cells and have a proliferative potential. In mutant rats for EGFR, there is reduction in branching morphogenesis.12 During initial bud stage, EGF is not present and TGF-[alpha] has the proliferative potential at this stage. EGF appears by early canalicular stage in the terminal end buds while TGF-[alpha] appears by late canalicular stage on that part of ductal epithelium which faces the lumen because this is the site where proliferation and apoptosis is very rapid at this stage.17 Developing salivary glands cells which secrete EGF are destined to become the ductal cells. EGF is absent in salivary acinar cells.18 EGF also positively regulates the effect of alpha-6 integrin. Alpha-6 integrin is located on the basal surface of epithelial cells and regulates branching morphogenesis.1,19

Extracellular matrix components that include glycosaminoglycans (GAGs), aforementioned alpha-6 integrin, fibronectin, cadherinsand collagens also regulate branching morphogenesis. These extracellular matrix components accumulate on the cleft site instead of the bud site.1,19 Fibronectin present in early epithelial buds induces cell-matrix adhesions on epithelial cells of salivary glands. During initial stages of development, E-cadherin and catenin regulate the morphogenesis of submandibular glands while during advanced stages of development, they make cell-cell junctions. Matrix components are remodeled continuously during branching morphogenesis. Degradation of GAG under the influence of matrix metalloproteinases (MMPs) provides more surface area for the epithelium to proliferate. During early development, chondroitin sulphate (CS) is the predominant GAG but with advanced development, chondroitin sulphate is replaced by heparin sulphate (HS).10,19

Matrix metalloproteinases (MMPs) not only degrade collagen, fibronectin and laminins but also activate heparin binding-epidermal growth factor (HB-EGF) which is also a ligand of EGFR and belongs to EGF family of cytokines. The accumulation and degradation of collagen is essential in cleft formation.20 If tissue inhibitor of metalloproteinase (TIMP) is added in vitro which degrades MMPs, it increases the number of clefts thus increasing branching.1,16,19,20

Initially, developing salivary gland structure is a solid cord. To function as a mature gland, it needs to be hollowed out to transfer saliva from acinar cells to the oral cavity. In order to develop a lumen, outer epithelial cells proliferate rapidly while central part undergoes apoptosis at the canalicular stage around E15.1 Tumor necrosis factor (TNF) is an important cytokine that regulates the balance between apoptotic activity and proliferative activity of salivary glands ductal epithelium. It binds to its receptor; tumor necrosis factor receptor (TNFR) which is expressed in the ductal epithelium and presumptive acinar cells. After binding to extracellular domain of TNFR, it either induces trimerisation to cause apoptosis or it activates NF-kB pathway to cause proliferation. This leads to the formation of lumen.1

Apoptotic activity in main salivary ducts for canalization is also mediated by caspases mainly by caspase-8.9 Salivary glands undergo further branching to reach the terminal bud stage at E17.1,19 Lumen formation of terminal buds is regulated by p53 protein. During canalization, apoptosis of surrounding epithelium is prevented by NF-KB, Bcl2, and Survivin which are anti-apoptotic proteins.9 Both blood vessels and nerves also start to develop around the developing gland.12 In addition to initial bud formation, Shh has a role in lumen formation. Eda is also involved in lumen formation of the developing buds.1 Lumen formation starts in the proximal part of main duct and continues towards the distal ends and finally in the terminal buds.14

The parasympathetic innervation plays an important role during salivary gland development and regeneration as it keeps progenitor cell population in an undifferentiated state so that these cells can be used when required during organogenesis.21 The parasympathetic nerves develop side by side along with the developing parenchyma of the salivary glands. Glial cell-derived neurotropin appears to be the main component for the development of the peripheral nerves in case of parasympathetic nerves. While nerve growth factor (NGF) plays a role in the development of sympathetic nerves. If parasympathectomy is done in initial stages of salivary gland development, a reduction in the size of gland is observed.17

Postnatal development of salivary glands:

The development of rodent salivary glands is not completed prenatally and to function as a mature gland, it develops further during postnatal period. The postnatal development of mouse salivary glands is completed by 45 days after birth22during which myoepithelial cells and granular convoluted tubules also develop. The granular convoluted tubules arise from striated ducts and are a part of them. The salivary glands of rats complete their morphological development by 7 to 10 weeks.23 Post-natal development of acinar cells is ahead of the postnatal development of ductal system.24

It is concluded that salivary glands pass through pre-natal development that involves pre-bud, initial bud, pseudo-glandular, canalicular and terminal bud stages and becomes fully functional post-natally. Molecules such as FGF, Shh, Eda, Edar, EGF, TNF, alpha-6 integrin play important role during their development. Extracellular matrix components such as fibronectin and matrix metalloproteinases also play a crucial role during development especially in developing cell to cell junctions. The parasympathetic nerve supply aids in normal development of the salivary glands. Disturbances in regulations of these molecules affect development of salivary glands which can result from mild structural defects to complete absence of salivary glands.

FUTURE PERSPECTIVES

This review discusses molecular signaling between epithelium and mesenchyme during prenatal developmental stages of salivary gland development. While much is known about pre-natal development, much research is needed to elucidate the molecular mechanisms involved in postnatal salivary gland development. Along with this, the role of blood vessels and nerves can also be further investigated. Further research should be directed to investigate how various molecules involved in preor post-natal development can be incorporated for regeneration of the salivary glands that may help ultimately to understand or treat the congenital disorders of salivary glands.

ACKNOWLEDGMENTS

The authors would like to thank the Higher Education Commission of Pakistan for providing e-Library access to the University through which acquisition of data was possible.

Author's Contribution

SB: Conceived, did acquisition of the published data and did manuscript writing. SG: Conceived, provided critical revisions through intellectual output, contributed to manuscript writing and did final approval of the manuscript.

Grant Support and Financial Disclosures

None to declare.

Conflict of Interest

The authors declare no conflict of interest

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Publication:Biomedica
Date:Sep 30, 2018
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