Overexpression of Brain-Derived Neurotrophic Factor Enhances Sensory Innervation and Selectively Increases Neuron Number

Abstract

Target-derived neurotrophin growth factors have significant effects on the development and maintenance of the mammalian somatosensory system. Studies of transgenic mice that overexpress neurotrophins NGF and neurotrophin 3 (NT-3) at high levels in skin have shown increased sensory neuron number and enhanced innervation of specific sensory ending types. The effects of two other members of this family, BDNF and NT-4, on sensory neuron development are less clear. This study examined the role of brain-derived neurotrophic factor (BDNF) using transgenic mice that overexpress BDNF in epithelial target tissues of sensory neurons. BDNF transgenic mice had an increase in peripheral innervation density and showed selective effects on neuron survival. Neuron number in trigeminal ganglia, DRG, and SCG were unchanged, although a 38% increase in neurons comprising the placode-derived nodose-petrosal complex occurred. BDNF transgenic skin showed notable enhancement of innervation to hair follicles as detected by PGP9.5 immunolabeling. In nonhairy plantar skin, Meissner corpuscle sensory endings were larger, and the number of Merkel cells with associated innervation was increased. In trigeminal ganglia, neurons expressing trkB receptor were increased threefold, whereas trkA-positive neurons doubled. Analysis of trkB by Northern, reverse transcription-PCR, and Western assays indicated a modest increase in the expression of the T1 truncated receptor and preferential distribution to the periphery. These data indicate that skin-derived BDNF does not enhance survival of cutaneous sensory neurons, although it does promote neurite innervation of specific sites and sensory end organs of the skin.

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

“…Experimental animals consisted of C57BL/6J wild-type mice (The Jackson Laboratory, Bar Harbor, ME) and transgenic mice that overexpress BDNF under the control of a cytokeratin-14 promoter/enhancer (BDNF-OE) (LeMaster et al, 1999) aged 6 -16 weeks. The transgenic mice have enhanced expression of BDNF in cells that express keratin 14 (K-14).…”

“…The neurotrophin family of neuronal growth factors (e.g., NT4, BDNF, NGF), or their molecular receptors, have been shown in nongustatory sensory systems to influence peripheral innervation, for example, innervation of the inner ear by eighth nerve ganglion cells (Schimmang et al, 1995), and innervation of cutaneous receptors by dorsal root ganglion cells (Fundin et al, 1997;LeMaster et al, 1999). Neurotrophins also influence the central growth of connections from peripheral sensory receptors to the brain (Buckland and Cunningham, 1998;Caminos et al, 1999;Patel et al, 2003).…”

Subpopulations of motor and sensory neurons respond differently to brain‐derived neurotrophic factor depending on the presence of the skeletal muscle

“…Therefore, this technique generates reliable estimates of cell number in the nervous system (Coggeshall, 1992;Clarke, 1993). An estimate of the number of proprioceptive cells in each LDRG (L3-L4) and TDRG (T4 -T6) was obtained by multiplying the average number of profiles per section by the length of the DRG (Davis et al, 1996;LeMaster et al, 1999).…”

Mathematical analysis of competition between sensory ganglion cells for neurotrophic factor in the skin

“…Fourth, even the developing sensory neurons that normally survive die if deprived of an essential trophic factor during the cell death period. For many sensory neurons including those expressing substance-P the trophic factor is NGF, but some classes of sensory neurons depend on other members of the NGF family (called ÔneurotrophinsÕ), notably BDNF and NT-3 [15][16][17][18][19][20], or members of other protein families [21]. Fifth, NGF-dependent sensory neurons obtain their NGF exclusively from their target territory, where it is synthesized, and remove it by retrograde transport in sufficiently large quantities to greatly deplete its concentration in the target [22,23].…”

“…Sixth, raising the concentration of NGF (or other neurotrophins) in the axonal target region above normal levels reduces neuronal death, causing ganglionic hypertrophy [6,7]. Most such experiments involved the systemic administration of exogenous trophic factor, but Albers et al [25,26] showed that transgenic mice overexpressing NGF in the epidermis (but not elsewhere) were subject to greatly reduced death of sensory ganglion neurons, and a similar approach has subsequently been used to show reduced ganglion neuron death following cutaneous overexpression of NT-3 [19] or BDNF [18].…”