Development and neuronal dependence of cutaneous sensory nerve formations: Lessons from neurotrophins

Montano, J.A; Pérez-Piñera, Pablo; García‐Suárez, Olivia; Cobo, Juan; Vega, J.A.

doi:10.1002/jemt.20790

Cited by 37 publications

(43 citation statements)

References 182 publications

(252 reference statements)

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“…to play an important role in normal maintenance, proliferation, and differentiation of not only cutaneous nerves, but also keratinocytes, melanocytes, and other cells in the skin (Marconi et al, 1999;Montano et al, 2010). Cellular responses to NGF are mediated by 2 classes of transmembrane receptors, a low-affinity receptor of ~75 kD (p75) (Johnson et al, 1986) and a highaffinity tyrosine kinase receptor of ~140 kD (TrkA) .…”

Section: Discussionmentioning

confidence: 99%

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Zhang¹,

Y²

2014

Genet. Mol. Res.

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ABSTRACT. Decades of research have provided the data to confirm the hypothesis that there is bidirectional communication between the central nervous system and the immune system in psoriasis pathogenesis, but the contribution of the cutaneous neural system remains underexplored. In this study, we evaluated the molecular mechanisms by which nerve growth factor (NGF) regulates hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) production. The mRNA and protein levels of VEGF secretion from HaCaT cells by NGF were increased in a concentration-dependent manner. In addition, the NGFinduced increase in VEGF is accompanied by an increase in HIF-1α, but not HIF-2α or HIF-1β. However, this increase is abrogated by pretreatment with a mammalian target of rapamycin (mTOR) inhibitor rapamycin. Pharmacologic inhibitors of the Trk tyrosine kinase, PI-3 kinase, and mTOR pathways prevent NGF-stimulated increases in HIF-1α and VEGF. Mutation of the siRNA-mediated silencing of HIF-1α expression blocks NGF-induced increases in VEGF transcription. Our 9325 NGF and VEGF in HaCaT keratinocytes©FUNPEC-RP www.funpecrp.com.br Genetics and Molecular Research 13 (4): 9324-9335 (2014) study indicates that NGF regulates the expression of VEGF through the PI3K/mTOR signaling pathway in human HaCaT keratinocytes.

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Section: Discussionmentioning

confidence: 99%

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Zhang¹,

Y²

2014

Genet. Mol. Res.

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“…Keratinocytes, the predominant epidermal cell type, are known to produce neurotrophic factors (NTFs) [21, 23, 33]. However, melanocytes also synthesize neurotrophic proteins [20].…”

Section: Introductionmentioning

confidence: 99%

Langerhans cells regulate cutaneous innervation density and mechanical sensitivity in mouse footpad

Doss

Smith

2014

Neuroscience Letters

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Langerhans cells are epidermal dendritic cells responsible for antigen presentation during an immune response. Langerhans cells associate intimately with epidermal sensory axons. While there is evidence that Langerhans cells may produce neurotrophic factors, a role in regulating cutaneous innervation has not been established. We used genetically engineered mice in which the diphtheria toxin (DT) receptor is targeted to Langerhans cells (Lang-DTR mice) to assess sensory axon-dendritic cell interactions. Diphtheria toxin administration to wild type mice did not affect epidermal structure, Langerhans cell content, or innervation density. A DT administration regimen supramaximal for completely ablating epidermal Langerhans cells in Lang-DTR mice reduced PGP 9.5–immunoreactive total innervation and calcitonin gene related peptide–immunoreactive peptidergic nociceptor innervation. Quantitative real-time polymerase chain reaction showed that epidermal gene expression of brain derived neurotrophic factor was unchanged, but nerve growth factor and glial cell line-derived neurotrophic factor mRNAs were reduced. Behavioral testing showed that, while thermal sensitivity was unaffected, mice depleted of Langerhans cells displayed mechanical hypersensitivity. These findings provide evidence that Langerhans cells play an important role in determining cutaneous sensory innervation density and mechanical sensitivity. This may involve alterations in neurotrophin production by Langerhans or other epidermal cells, which in turn may affect mechanical sensitivity directly or as a result of neuropathic changes.

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“…Indeed, null mutations of genes from the NGF family of NT and their receptors (NTRs) lead to loss/reduction of specific neurons in sensory ganglia; conversely, cutaneous overexpression of NT results in skin hyperinnervation and increase in the number of sensory neurons innervating the skin. 22 In addition, NGF synthesized in the epidermis, is retrogradelly transported to the ganglia to stimulate the release of neuropeptides in the skin, thus favoring cutaneous neurogenic inflammation. 23 Subsequently, it became clear that NGF possesses a number of biological effects also on non-neuronal cells.…”

Section: Neurotrophins and The Skinmentioning

confidence: 99%

Neurotrophins in healthy and diseased skin

Truzzi

Marconi

Pincelli

2011

Dermato-Endocrinology

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Neurotrophins and Their ReceptorsNeurotrophins (NT) belong to a group of functionally and structurally related proteins that were first identified as promoters for neuronal survival. Subsequently, it was demonstrated that they regulate many aspects of neuronal development and function, like synapse formation and synaptic plasticity.1 Nerve growth factor (NGF) was the first NT to be discovered during a search for survival factors.2 Brain-derived neurotrophic factor (BDNF) was the second NT to be characterized. It has been identified as a survival factor for several neuronal populations not responsive to NGF.3 These two proteins revealed conserved features of the sequences, leading to isolation of clones encoding additional members of this family.Nowadays, we know that four NT are expressed in mammals: NGF, BDNF, NT-3 NT-4. NT play a critical role in developmental neurobiology. They play an essential role in cellular interactions, in controlling cell survival and differentiation. 4 NGF is internalized by receptor-dependent mechanisms and transported along axons in membranous vesicles and energy-dependent processes. Neurotrophins (NT) belong to a family of structurally and functionally related proteins that, depending on the tissue context and the receptors involved, promote either neuronal cell survival and differentiation or cell death. NT, and in particular NGF, were first identified as neurotrophic factors supporting the synthesis and development of sensory neurons in the central and peripheral nervous system. it is now widely accepted that NT also act as growth factors in non-neuronal cells, including the skin. in the skin, most cell types are able to secrete and/or to respond to stimulation by NT, creating a unique network of molecular signaling in the cutaneous microenvironment. Moreover, many skin diseases have been associated with an involvement of a number of neural factors including NT, but less attention has been given to the role of NT as growth factors in the development of skin pathologies. This review summarizes currently data on the expression and function of NT and their receptors in several cell types in the skin. Moreover it focuses on the role of the skin NT network in two cutaneous conditions, melanoma and psoriasis where NT are clearly involved.

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Development and neuronal dependence of cutaneous sensory nerve formations: Lessons from neurotrophins

Cited by 37 publications

References 182 publications

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Nerve growth factor regulates the expression of vascular endothelial growth factor in human HaCaT keratinocytes via PI3K/mTOR pathway

Langerhans cells regulate cutaneous innervation density and mechanical sensitivity in mouse footpad

Neurotrophins in healthy and diseased skin

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