On functions of neurotrophic factors in taste buds and teeth

Background: Chemosensory disorders affect approximately 15% of the U.S. population and an estimated 200,000 individuals visit a doctor each year for problems with their ability to taste or smell (NIDCD). Among the common causes of taste problems are radiation therapy, chemotherapy, exposure to certain chemicals and medications, head trauma and surgical injuries. Tastants are detected by taste buds, which are specialized collections of cells. Taste bud development and innervation has been an active research front and several key molecules involved in these processes have been elucidated. Neurotrophins, in particular brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were among the first to be identified as playing a role in taste buds. BDNF and NT-3 are expressed in developing and adult rodent tongues in a temporospatially specific manner. BDNF mRNA is found in the gustatory epithelium during development and in adult taste buds, NT-3 mRNA in the surrounding epithelium in rodents. Neurotrophins are also expressed in a temporospatially specific manner during tooth morphogenesis. Nerve growth factor (NGF), BDNF and glial cell line-derived neurotrophic factor (GDNF) are expressed in developing rodent teeth.

Aims: To examine the expression of mRNA encoding neurotrophic factors in the developing human taste system and teeth, to assess the role of neurotrophic factors in the formation and innervation of taste buds and teeth, and to explore possible consequences of neurotrophic factor expression in cultured dental pulp cells (DPCs).

Results: Neurotrophic factor expression patterns are described in the developing human tongue and compared to those of rodents. BDNF was found in the first-trimester in the same areas as in rodents; developing gustatory epithelium and taste buds, and in additional areas such as the subepithelial mesenchyme. Human NT-3 mRNA expression patterns were largely similar to those of rodents, except that taste buds also expressed NT-3 mRNA during development and in adults. In both rodents and humans, BDNF was expressed prior to innervation of gustatory papillae, and thus serves as a very early marker of the gustatory epithelium. Our study showed wider expression patterns of both BDNF and NT-3 in the human gustatory system (paper I) compared to rodents. Next, we showed that taste papillae in BDNF/NT-3 double KO mice were smaller and less innervated compared to BDNF-/- mice, indicating specific gustatory roles for both neurotrophins (paper V). Studies of developing human teeth showed that NGF, BDNF, NT-3, neurotrophin-4 (NT-4), GDNF and neurturin (NTN) were expressed in the tooth organ and surrounding mesenchyme (paper III). Interactions of neurotrophic factors from the dental pulp and trigeminal, motor and dopamine (DA) neurons were analyzed. DPCs promoted survival and neurite outgrowth from trigeminal neurons in cocultures, and prolonged neural survival in vitro. DPCs also promoted motoneuron survival in a rodent model of spinal cord injury (paper II), as well as the survival of embryonic DA neurons in vitro (paper IV).

BDNF is the main neurotrophic factor in the gustatory system, but NT-3 plays a role as well in both humans and rodents, which knockout studies were able to detect. The tooth provides an excellent model to study molecular events in cells during organ formation, and to examine how neurotrophic factors promote innervation during development.

List of scientific papers

I. Nosrat IV, Lindskog S, Seiger A, Nosrat CA. Lingual BDNF and NT-3 mRNA expression patterns and their relation to innervation in the human tongue: Similarities and differences compared with rodents. Journal of Comparative Neurology. 2000, 417:133-52.
https://doi.org/10.1002/(SICI)1096-9861(20000207)417:2<133::AID-CNE1>3.0.CO;2-I

II. Nosrat IV, Widenfalk J, Olson L, Nosrat CA. Dental pulp cells produce neurotrophic factors, interact with trigeminal neurons in vitro, and rescue motoneurons after spinal cord injury. Developmental Biology. 2001, 238:120-32.
https://doi.org/10.1006/dbio.2001.0400

III. Nosrat I, Seiger A, Olson L, Nosrat CA. Expression patterns of neurotrophic factor mRNAs in developing human teeth. Cell & Tissue Research. 2002, 310:177-87.
https://doi.org/10.1007/s00441-002-0618-8

IV. Nosrat IV, Smith CA, Mullally P, Olson L, Nosrat CA. Dental pulp cells provide neurotrophic support for dopaminergic neurons and differentiate into neurons in vitro; implications for tissue engineering and repair in the nervous system. European Journal of Neuroscience. 2004, 19:2388-98.
https://doi.org/10.1111/j.0953-816X.2004.03314.x

V. Nosrat IV, Agerman K, Marinescu A, Ernfors P, Nosrat CA. Lingual deficits in neurotrophin double knockout mice. Journal of Neurocytology. 2004, 33:607-15.
https://doi.org/10.1007/s11068-005-3330-2