Epithelial Overexpression of BDNF or NT4 Disrupts Targeting of Taste Neurons That Innervate the Anterior Tongue

Abstract

Brain-derived neurotrophic factor (BDNF) and neurotrophin-4 (NT4) are essential for the survival of geniculate ganglion neurons, which provide the sensory afferents for taste buds of the anterior tongue and palate. To determine how these target-derived growth factors regulate gustatory development, the taste system was examined in transgenic mice that overexpress BDNF (BDNF-OE) or NT4 (NT4-OE) in basal epithelial cells of the tongue. Overexpression of BDNF or NT4 caused a 93 and 140% increase, respectively, in the number of geniculate ganglion neurons. Surprisingly, both transgenic lines had severe reduction in fungiform papillae and taste bud number, primarily in the dorsal midregion and ventral tip of the tongue. No alterations were observed in taste buds of circumvallate or incisal papillae. Fungiform papillae were initially present on tongues of newborn BDNF-OE animals, but many were small, poorly innervated, and lost postnatally. To explain the loss of nerve innervation to fungiform papillae, the facial nerve of developing animals was labeled with the lipophilic tracer DiI. In contrast to control mice, in which taste neurons innervated only fungiform papillae, taste neurons in BDNF-OE and NT4-OE mice innervated few fungiform papillae. Instead, some fibers approached but did not penetrate the epithelium and aberrant innervation to filiform papillae was observed. In addition, some papillae that formed in transgenic mice had two taste buds (instead of one) and were frequently arranged in clusters of two or three papillae. These results indicate that target-derived BDNF and NT4 are not only survival factors for geniculate ganglion neurons, but also have important roles in regulating the development and spatial patterning of fungiform papilla and targeting of taste neurons to these sensory structures.

Mice lacking the p75 receptor fail to acquire a normal complement of taste buds and geniculate ganglion neurons by adulthood

“…Within the lingual epithelium, BDNF is specifically expressed in fungiform papillae. This expression pattern is critical for successful innervation of taste epithelia by gustatory neurons (Ringstedt et al, 1999;Krimm et al, 2001), suggesting that BDNF plays a chemotactic role during the final stages of axon targeting. The p75 receptor is also important for neurotrophin regulation of growth cone dynamics in vitro Gehler et al, 2004).…”

“…Fungiform papillae are also lost in NT4 À/À mice, but circumvallate papilla are normal (Liebl et al, 1999). In addition, mice that overexpress BDNF or NT4 in the lingual epithelium have twice the number of geniculate neurons normally observed in adults (Krimm et al, 2001). These findings demonstrate that BDNF and NT4 are required for survival of gustatory neurons and taste buds during development.…”

Exuberant Neuronal Convergence onto Reduced Taste Bud Targets with Preservation of Neural Specificity in Mice Overexpressing Neurotrophin in the Tongue Epithelium

“…The anterior tongue taste system in mouse is ideal for evaluating this because the normal receptoneural pattern is remarkably precise, more so than in other rodents whose ganglion cell peripheral fibers branch considerably (Miller, 1971(Miller, , 1974Whitehead et al, 1999;Zaidi and Whitehead, 2006). In the present study, the innervation pattern was examined in mice that overexpress BDNF in the lingual epithelium, both around taste buds and at filiform papillae (Krimm, 2001). These BDNF-overexpressing (OE) mice have a dramatically altered taste phenotype (i.e., one-third the number of fungiform taste buds and, paradoxically, twice normal numbers of geniculate ganglion cells) (Krimm, 2001).…”

“…Brainderived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3), and their receptors, are expressed in taste bud-bearing lingual papillae and their innervating ganglion cells Olson, 1995, 1998;Nosrat et al, 1996Nosrat et al, , 2000Nosrat et al, , 2001Farbman et al, 2004). Gemmal and ganglion cell numbers are disrupted in the absence or overexpression of BDNF, or its receptor, tyrosine kinase B (TrkB) (Fritzsch et al, 1997;Nosrat et al, 1997;Cooper and Oakley, 1998;Oakley et al, 1998;Mistretta et al, 1999;Ringstedt et al, 1999;Krimm et al, 2001;Sun and Oakley, 2002). Thus, neurotrophins and their receptors influence, somehow, the development and maintenance of peripheral neural elements in taste as in other sensory systems (Schimmang et al, 1995;Fundin et al, 1997;Buckland and Cunningham, 1998;Caminos et al, 1999).…”

Roles of innervation in developing and regenerating orofacial tissues

“…Defective gustatory innervation leads to an important reduction of taste buds in foliate and circumvallate papillae, with a subsequent impairment of taste [23]. Conversely, specifically driven overexpression of BDNF in taste buds of adult animals increases gustatory innervation, which results in wider taste buds with supernumerary cells when compared to those of wild type animals [25]. A less severe loss of gustatory innervation and taste buds has been observed in NT4 knock out mice [24].…”