Molecular development of the extrinsic sensory innervation of the gastrointestinal tract

Abstract

The extrinsic sensory innervation of the gastrointestinal tract is the conduit through which the gut and the central nervous system communicate. The hindbrain receives information directly from the bowel via the vagus nerve, while information from spinal afferents arrives in the central nervous system through the dorsal root ganglia. This review focuses on the molecular development of these vagal and spinal innervations, with an emphasis on mechanisms that involve axon guidance. During development, axons from both the nodose ganglia and dorsal root ganglia grow into the gut, innervate their appropriate enteric targets and avoid inappropriate cells in the gut wall. These developmental outcomes suggest that both attractive and repellent molecules are important in establishing the normal pattern of the extrinsic sensory innervation. In the fetal mouse gut, the guidance of vagal sensory axons is mediated by axon guidance molecules, such as netrin and the netrin receptor, deleted in colorectal cancer (DCC), as well as extracellular matrix molecules, such as laminin-111. Dorsal root ganglion neurons are known to express, and their axons to respond to, axon guidance molecules. The question of whether or not these molecules are involved in guiding spinal afferents to the bowel, however, has not yet been examined. It is anticipated that a better understanding of how vagal and spinal afferents innervate the fetal gut and reach specific enteric locations will provide deeper insights into the underlying mechanisms of normal and abnormal sensation from the gastrointestinal tract.

Peritoneal innervation: embryology and functional anatomy

“…ENS consists of a mesh-like system of neurons derived from the neural crest cells [2]. Since the embryonic gut and its appendages arise as midline organs, their splanchnic innervation is bilateral, and accordingly, visceral pain is perceived in the midline.…”

“…During embryogenesis, axons from both the nodose ganglia and dorsal root ganglia grow into the gut to form the extrinsic innervation. Once they have reached the enteric organs, vagal sensory axons appropriate enteric cells and grow to provide innervation to four locations [2]: -Myelinated and unmyelinated fibers terminating in the submesothelial tissue directly under the bowel serosa, -Intramuscular arrays (IMA) located between the cells of the external muscle, probably stretch receptors, -Large intraganglionic laminar endings (IGLEs) associated with the connective tissue sheaths of ganglia [17]; tension in the gut wall activates IGLEs [15], -Sensory endings within the lamina propria of the mucosa; the sensory projections in the lamina propria correspond to functional mucosal receptors.…”

“…While sympathetic and parasympathetic pathways overlap for the majority of the length of the bowel, the vagal afferents are thought to signal mainly from the upper gastrointestinal regions and the pelvic afferents from the colorectal region. Vagal afferent neurons project viscerotopically to the brain (precisely into the nucleus of the solitary tract in the medulla oblongata) via the nodose ganglia (reviewed in [2]). …”

“…Receptors of the extrinsic nerves are sensitive to pressure, friction, cutting and burning and are therefore comparable to cutaneous receptors. Such sensory information is conveyed from the gastrointestinal organs to the CNS by two separate extrinsic pathways: -the vagus nerve, conveying the information directly from the bowel to the hindbrain, -spinal afferents transmitting sensory innervation indirectly through the dorsal root ganglia and the spinal cord [2]. Visceral sensory afferents are almost exclusively thinly myelinated Aδ-fibres and unmyelinated C-fibers [18].…”

“…Gastrointestinal homeostasis, nutrition and health are dependent on the coordination between the intrinsic nervous system, functioning largely without information to the central nervous system (CNS), with the extrinsic innervation [1], which provides communication between the bowel and the CNS (reviewed in [2]). Aim of this review is to provide the reader with fundamental understanding of the innervation of the peritoneum, integrating textbook knowledge and recent advances in the field.…”