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

Abstract

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.

The Meissner and Pacinian sensory corpuscles revisited new data from the last decade

“…Conversely, overexpression of some neurotrophins in the target organs of specific neurons leads to an increase in the density of corpuscles without affecting the number of neurons in DRG, which suggest that local factors are involved in the development of sensory corpuscles. These approaches allowed the classification of specific subtypes of cutaneous, hair associated or muscular mechanoreceptors according to the neuronal classes on which they depend (Botchkarev et al, 1999;Cronk et al, 2002;de Carlos et al, 2006;Ernfors et al, 1994a,b;Fariñ as et al, 1994;Fundin et al, 1997;Gonzalez-Martinez et al, 2004Ichikawa et al, 2000Ichikawa et al, , 2001Krimm et al, 2006;LeMaster et al, 1999;Matsuo et al, 2001;Pérez-Piñ era et al, 2008;Sedy et al, 2004).…”

“…Most of the cutaneous mechanoreceptors with express some of the DEG/ENaC members are dependent on TrkB and their ligands BDNF and NT-4 (de Carlos et al, 2006;Gonzalez-Martínez et al, 2004Krimm et al, 2006;LeMaster et al, 1999;Perez-Piñ era et al, 2008), and TrkC and NT-3 (Airaksinen et al, 1996;Sieber-Blum et al, 2004). Interestingly, NT-3 causes increase in the expression ASIC 1 and 3 (McIlwrath et al, 2007).…”

Role of neurotrophin signalling in the differentiation of neurons from dorsal root ganglia and sympathetic ganglia

“…Mutation of NT4 reduces the proportion of trkB-expressing and increases that of trkC-expressing DRG neurons in newborn mice (Liebl et al 2000). In adult NT4-overexpressing animals, the opposite alterations are observed (Krimm et al 2006). The mechanism of this effect still needs to be resolved.…”

Neurite Outgrowth andIn VivoSensory Innervation Mediated by a CaV2.2–Laminin β2 Stop Signal

“…Growth of sensory neurites is mediated by neurotrophic factors such as NT-4 (Krimm et al, 2006) and guidance molecules such as ephrins (Moss et al, 2005). Branching and tiled patterning of sensory neurites relies on the NDR (nuclear Dbf2-related) kinase family in both like-repels-like tiling (Emoto et al, 2006) and noncontactmediated distribution (Gallegos and Bargmann, 2004).…”