Neurotrophin-3 in the development of the enteric nervous system

Abstract

To date, the only neurotrophin that has been shown to influence the development of the enteric nervous system (ENS) is neurotrophin-3 (NT-3). NT-3 plays an essential role in the development of both the neural-crest-derived peripheral nervous system and the central nervous system (i.e., Chalazonitis, 1996, Mol. Neurobiol., 12: 39-53; Sieber-Blum, 1999, Neurotrophins and the Neural Crest, CRC Press, Boca Raton). This review integrates data obtained from our laboratory and from our collaboration with other investigators that demonstrate a late-acting role for NT-3 in the development of enteric neurons in vitro and in vivo. Studies of the biological actions of NT-3 on enteric neuronal precursors in vitro demonstrate that NT-3 acts directly on the precursor cells and that it also acts in combination with other neurotrophic factors such as glial cell line-derived neurotrophic factor and a ciliary neurotrophic factor-like molecule, to promote the survival and differentiation of enteric neurons and glia. Importantly, bone morphogenetic protein-2 (BMP-2) and BMP-4, members of the transforming growth factor-beta (TGF-beta) superfamily, regulate the onset of action of NT-3 during fetal gut development. Analyzes performed on mice deficient in the genes encoding NT-3 or its transducing tyrosine kinase receptor, TrkC, and conversely on transgenic mice that overexpress NT-3 substantiate a physiological role for NT-3 in the development and maintenance of a subset of enteric neurons. There is loss of neurons in both the myenteric and submucosal plexuses of mice lacking NT-3/TrkC signaling and selective hyperplasia in the myenteric plexus of mice overexpressing NT-3. Analyzes performed on transgenic mice that overexpress noggin, a specific BMP-4 antagonist, show significant decreases in the density of TrkC-expressing neurons but significant increase in overall neuronal density of both plexuses. Conversely, overexpression of BMP-4 is sufficient to produce, an increase in the proportion of TrkC-expressing neurons in both plexuses. Overall, our data point to a regulatory role of BMP-4 in the responses of subsets of myenteric and submucosal neurons to NT-3. NT-3 is required for the differentiation, maintenance and proper physiological function of late-developing enteric neurons that are important for the control of gut peristalsis.