Neurothrophins in the development of the gustatory system and teeth

Abstract: Flavors of taste are detected by a set of microscopical cellular aggregates calledthe taste buds, present in different arrangements on the upper surface of the tongueand other areas in the mouth. Taste buds are chemosensors that can detect differenttaste qualities such as sweet, sour, bitter, salt and umami. Information from thetaste buds is carried via nerve fibers to the brain where these signals are furtherprocessed, finally leading to the experience of taste. Taste buds not only help usenjoy food, they are also part of an important control and warning system, enablingus to avoid consuming hazardous substances or spoiled food. During the past severalyears, more light has been shed on many aspects of the gustatory system, includingthe local epithelial origin of taste buds and taste transduction mechanisms. However,the manner in which taste buds develop and become connected to the brain by nervefibers has long been a matter of debate. The present work now demonstrates the crucialimportance of two proteins closely related to nerve growth factor (NGF) in tastebud development and proper taste and sensory functions of the mouth. Messenger RNAcoding for the NGF-related proteins BDNF (brain derived neuro trophic factor) andNT-3 (neurotrophin-3) were found to be present in precisely the right locations inand around the taste buds to suggest that they are of vital importance for controllingthe arrival of nerve fibers to these structures. These hypotheses were borneout bystudies of mice in which either the gene for BDNF or NT-3 had been selectively turnedoff. Mice that developed without BDNF had very few and abnormal taste buds and wereunable to discriminate between primary tastes such as sweet, salt or bitter. Animalsin which the NT-3 gene had instead been turned off appeared to have a normal developmentof their taste bud system, but instead demon strated severe impairment of sensoryfunction of mucous membranes of the oral cavity. These results demonstrate key roles for the two neurotrophic proteins BDNF andNT-3 in con trolling the development of the gustatory and somatosensory apparatusesof the mouth. These neurotrophins also seem to be important in oral gustatory andsomatosensory innervation in humans. It remains to be seen whether or not disturbancesof the genes for these neurotrophic proteins might underlie rare human conditionssuch as familial dysautonomia in which the ability to discriminate tastes is lost.These novel findings may also have implications in more common cases in problemsof loss of taste and sensation in the mouth such as those seen after injury to thenerves, either by accident or following oral or facial surgery. Knowledge about whichproteins are needed to stimulate nerve fibers to grow into mucous membranes of theoral cavity during development suggests that these same proteins might become helpfulin stimulating regeneration of injured nerves in adult patients, perhaps helpingthem to regain lost taste and sensory function. Neurotrophins are also expressed in the developing teeth. They all show temporospatiallyspecific expression patterns. We suggest that neurotrophins are involved in earlymorphogenetic events during tooth development and that NGF and BDNF are involvedin the innervation of the dental pulp. Further experiments are required to determinethe precise roles of neurotrophins in tooth development. The GDNF family of ligands and receptors are also expressed in developing tongueand teeth. They might be involved in the autonomic innervation ot the tongue. Inteeth, they might partici pate both in morphogenetic events during tooth developmentand participate in tooth innervation. Keywords: Gustation, gustatory, taste buds, neurotrophins, NGF, BDNF, NT-3, NT-4,GDNF, GFRalpha-l, GFRalpha-2, knockout, innervation, development, tooth, tooth development,odontogene sis. Christopher A. Nosrat, 1997 ISBN 91-628-2795-2