Interactions between developing nerves and salivary glands

Abstract

Our aim is to provide a summary of the field of salivary gland development and regeneration from the perspective of what is known about the function of nerves during these processes. The primary function of adult salivary glands is to produce and secrete saliva. Neuronal control of adult salivary gland function has been a focus of research ever since Pavlov's seminal experiments on salivation in dogs. Less is known about salivary gland innervation during development and how the developing nerves influence gland organogenesis and regeneration. Here, we will review what is known about the communication between the autonomic nervous system and the epithelium of the salivary glands during organogenesis. An important emerging theme is the instructive role of the nervous system on the epithelial stem/progenitor cells during development as well as regeneration after damage. We will provide a brief overview of the neuroanatomy of the salivary glands and discuss recent literature that begins to integrate neurobiology with epithelial organogenesis, which may provide paradigms for exploring these interactions in other organ systems.

Keywords: cholinergic signaling; epithelial progenitors; innervation; neurturin; parasympathetic innervation; salivary gland.

Figure 1. Model of parasympathetic and sympathetic innervation of the adult major salivary glands (in red and blue, respectively). Neurotransmitters for parasympathetic (red) and sympathetic fibers (blue): ACh acetylcholine, NPY neuropeptide Y, VIP vasoactive intestinal peptide, NA noradrenaline, SP substance P, CGRP calcitonin gene-related peptide. Brain stem nuclei: SSN superior salivatory nuclei, ISN inferior salivatory nuclei, Ganglia: ThG thoracic ganglion, SCG superior cervical ganglion, OG otic ganglion, SG submandibular ganglion. Spinal cord: C cervical vertebra, T thoracic vertebra; Cranial nerves: VII facial nerve, IX glossopharyngeal nerve.

Figure 2. Differential expression of genes associated with parasympathetic and sympathetic innervation during salivary gland development from SGMAP (http://sgmap.nidcr.nih.gov/sgmap/sgexp.html) Gene expression, normalized to the housekeeping gene 29S, was measured microarray, over a developmental time course from E11.5 to adult (Ad). AdF: adult female; AdM: adult male; E: embryonic day; P: postnatal day.

Figure 3. NRTN treatment improves epithelial morphogenesis after IR by reducing apoptosis of the PSG neurons. Top panels are brightfield images of E13 SMGs with or without IR and pre-treatment with recombinant NRTN. SMGs were visualized after 96h of culture. Red boxes show the approximate location used to image the PSG below. Scale bar: 500μm. Lower panels are confocal analysis of the PSG. Immunostaining for PSG with neural tubulin antibody (Tubb3 red), for apoptotic cells with Caspase 3 (Casp3, green), for nuclei with Hoechst. The bottom panels are merged images. Scale bar: 10μm.