Biomedical subjects

Robin F Krimm

Publications and source records attributed to Robin F Krimm.

6 recordsLinked to original sources

PubMed2006

Overexpression of neurotrophin 4 in skin enhances myelinated sensory endings but does not influence sensory neuron number.

The growth factors neurotrophin 4 (NT4) and brain-derived neurotrophic factor (BDNF) are expressed in the developing skin, activate the trkB tyrosine kinase receptor, and influence the development and survival of specific types of sensory afferents. Whether each factor is capable of regulating the same or overlapping populations of cutaneous afferents during development is unknown. A previous study of mice overexpressing BDNF in the developing skin (BDNF-OE mice) revealed that these animals exhibited increased hair follicle innervation, Meissner corpuscle size, and Merkel cell number in glabrous skin, although no change in the total number of sensory neurons was observed. To determine if NT4 affects cutaneous innervation in a manner similar to BDNF, transgenic mice overexpressing NT4 in skin, under the control of the keratin 14 gene promoter, were examined. Similar to BDNF-OE mice, NT4-OE mice had increased innervation to the skin but no increase in sensory neuron number in either the dorsal root ganglion or trigeminal ganglion. NT4 overexpression also enhanced hair follicle innervation and the size and density of innervation to Meissner corpuscles. Unlike BDNF overexpression, NT4 overexpression did not alter the number of Merkel cells in the glabrous skin, but it did enhance the number of myelinated axons in nerves projecting to skin. Thus, the same pattern of BDNF and NT4 overexpression within the skin produces phenotypes that are both similar and distinctive.

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PubMed2006

Refinement of innervation accuracy following initial targeting of peripheral gustatory fibers.

During development, axons of the chorda tympani nerve navigate to fungiform papillae where they penetrate the lingual epithelium, forming a neural bud. It is not known whether or not all chorda tympani axons initially innervate fungiform papillae correctly or if mistakes are made. Using a novel approach, we quantified the accuracy with which gustatory fibers successfully innervate fungiform papillae. Immediately following initial targeting (E14.5), innervation was found to be incredibly accurate: specifically, 94% of the fungiform papillae on the tongue are innervated. A mean of five papillae per tongue were uninnervated at E14.5, and the lingual tongue surface was innervated in 17 places that lack fungiform papillae. To determine if these initial errors in papillae innervation were later refined, innervation accuracy was quantified at E16.5 and E18.5. By E16.5 only two papillae per tongue remained uninnervated. Innervation to inappropriate regions was also removed, but not until later, between E16.5 and E18.5 of development. Therefore, even though gustatory fibers initially innervate fungiform papillae accurately, some errors in targeting do occur that are then refined during later embryonic periods. It is likely that trophic interactions between gustatory neurons and developing taste epithelium allow appropriate connections to be maintained and inappropriate ones to be eliminated.

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PubMed2006

Epithelial overexpression of BDNF and NT4 produces distinct gustatory axon morphologies that disrupt initial targeting.

Most fungiform taste buds fail to become innervated when BDNF or NT4 is overexpressed in the basal layer of tongue epithelium. Here, we examined when and how overexpression of BDNF and NT4 disrupt innervation to fungiform papillae. Overexpression of either factor disrupted chorda tympani innervation patterns either before or during the initial innervation of fungiform papillae. NT4 and BDNF overexpression each disrupted initial innervation by producing different gustatory axon morphologies that emerge at distinct times (E12.5 and E14.5, respectively). Chorda tympani nerve branching was reduced in NT4 overexpressing mice, and neuronal fibers in these mice were fasciculated and remained below the epithelial surface, as if repelled by NT4 overexpression. In contrast, many chorda tympani nerve branches were observed near the epithelial surface in mice overexpressing BDNF, and most were attracted to and invaded non-taste filiform papillae instead of gustatory papillae. These results suggest that BDNF, but not NT4, normally functions as a chemoattractant that allows chorda tympani fibers to distinguish their fungiform papillae targets from non-gustatory epithelium. Since BDNF and NT4 both signal through the p75 and TrkB receptors, trophin-specific activation of different internal signaling pathways must regulate the development of the distinct gustatory axon morphologies in neurotrophin-overexpressing mice.

Animals↗

PubMed2006

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

Brain-derived neurotrophic factor and neurotrophin-4 are required for normal taste bud development. Although these neurotrophins normally function via the tyrosine kinase receptor, trkB, they also bind to the pan-neurotrophin receptor, p75. The goal of the present study was to determine whether the p75 receptor is required for the development or maintenance of a full complement of adult taste buds. Mice with p75 null mutations lose 34% of their circumvallate taste buds, 36% of their fungiform papillae, and 26% of their fungiform taste buds by adulthood. The reduction of taste buds in the adult circumvallate papilla was similar to that observed previously at postnatal day 7 (Fan et al. Brain Res Dev Brain Res 2004;150:23-39). Taken together, these findings indicate that the p75 receptor is critical for the development of a full complement of taste buds, but is not required for maintenance of circumvallate taste buds in adulthood. Immunolabeling for p75 was not observed in taste buds, indicating that p75 signaling influences taste bud number indirectly. Geniculate ganglion neurons, which provides innervation to fungiform taste buds, express the p75 receptor. Mice with p75 null mutations also have fewer neurons in the geniculate ganglion. Together, these results suggest that the p75 receptor is important for the survival of geniculate neurons and geniculate neuron survival is required for the development of a full complement of taste buds by adulthood.

Aging↗

PubMed2004

Neuron/target plasticity in the peripheral gustatory system.

Taste bud volume on the anterior tongue in adult rats is matched by an appropriate number of innervating geniculate ganglion cells. The larger the taste bud, the more geniculate ganglion cells that innervate it. To determine if such a match is perturbed in the regenerated gustatory system under different dietary conditions, taste bud volumes and numbers of innervating neurons were quantified in adult rats after unilateral axotomy of the chorda tympani nerve and/or maintenance on a sodium-restricted diet. The relationship between taste bud size and innervation was eliminated in rats merely fed a sodium-restricted diet; individual taste bud volumes were smaller than predicted by the corresponding number of innervating neurons. Surprisingly, the relationship was disrupted in a similar way on the intact side of the tongue in unilaterally sectioned rats, with no diet-related differences. The mismatch in these groups was due to a decrease in average taste bud volumes and not to a change in numbers of innervating ganglion cells. In contrast, individual taste bud volumes were larger than predicted by the corresponding number of innervating neurons on the regenerated side of the tongue; again, with no diet-related differences. However, the primary variable responsible for disrupting the function on the regenerated side was an approximate 20% decrease in geniculate ganglion cells available to innervate taste buds. Therefore, the neuron/target match in the peripheral gustatory system is susceptible to surgical and/or dietary manipulations that act through multiple mechanisms. This system is ideally suited to model sensory plasticity in adults.

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PubMed2004

NT3 expressed in skin causes enhancement of SA1 sensory neurons that leads to postnatal enhancement of Merkel cells.

To determine the role of NT3 in the postnatal maturation of Merkel cell (MC) sensory neurite complexes (touch domes), we examined the development of their neural and end-organ components in wild-type and transgenic mice that overexpress NT3 (NT3-OE). Touch domes are sensory complexes of the skin that contain specialized MCs innervated by slowly adapting type 1 (SA1) neurons. Touch domes are dependent on NT3 and, though formed in newborn mice that lack NT3, are severely depleted during postnatal maturation. Mice that overexpress NT3 in the skin have larger touch domes characterized by enhanced neural innervation and MC number. In this study, we asked how this NT3-mediated enhancement occurs, whether through stimulatory effects of NT3 on the SA1 neuron, or the MC, or both. The innervation density and number of MCs associated with each touch dome were measured in wild-type and transgenic animals at postnatal times. In newborn NT3-OE mice, touch dome innervation was enhanced. Surprisingly, however, the number of MCs was lower in newborn NT3-OE animals than in wild-type littermates, and equivalent numbers were not reached until postnatal day 8 (PN8). Not until the PN12 and PN16 time points did MCs increase in NT3-OE mice. To examine the neural dependence of MCs in NT3-OE mice, touch domes were chronically denervated by resecting dorsal cutaneous nerves. Both wild-type and NT3-OE animals showed similar depletion in the number of MCs associated with touch domes. These data indicate that NT3 is not a survival factor for MCs and that the NT3-mediated enhancement of MC number is indirect and neurally dependent.

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