Keratinocyte Cytokine Networks Associated with Human Melanocytic Nevus Development

Abstract

Melanocytes can group together in nevi, commonly thought to form because of intrinsic somatic mutations involving MAPK pathway activation. However, the role of the microenvironment, in particular keratinocytes, in nevogenesis is rarely studied. Melanocytes proliferate during the hair follicle growth phase and in some basal cell carcinomas, allowing us to construct keratinocyte gene expression clusters correlated with melanocyte activation. We asked whether such correlations are evident in the more subtle context of regulation of melanocyte behavior in normal skin. We considered genes which, when mutated in keratinocytes in mice, lead to nevogenesis. Across the human GTEx normal skin database, their expression was correlated with that of keratinocyte cytokines KITLG, HGF, FGF2, EDN1, and melanocyte markers. These cytokines have pleiotropic effects on melanocyte-specific and pigmentation genes and also influence mast cell gene expression. We show five classes of keratinocyte genes that, via germline genetic variation, influence melanocyte activity. These include genes involved in SHH signaling, structural keratins, ribosomal biogenesis, and stem cell governance. In agreement with the finding of KITLG linked to nevogenesis in human genome-wide association studies, we provide evidence that specific keratinocyte cytokines are components of networks that may drive or exacerbate nevus development.

TRPS1 mutation associated with trichorhinophalangeal syndrome type 1 with 15 supernumerary teeth, hypoplastic mandibular condyles with slender condylar necks and unique hair morphology

“…In fact, this is supported by a study showing that transgenic mice with a constitutive activated RET have a prolonged anagen phase of hair follicles along with accelerated melanin production in and around hair bulbs 14 . Upregulation of Shh and Edn1 in keratinocytes has been shown to cause hyperpigmentation and hypertrichosis 15 . Therefore, SHH and EDN1 could also play a role in the hypertrichosis reported herein.…”

“…14 Upregulation of Shh and Edn1 in keratinocytes has been shown to cause hyperpigmentation and hypertrichosis. 15 Therefore, SHH and EDN1 could also play a role in the hypertrichosis reported herein. However, the rolling up of the scale edges of the hair cuticles, double mental foramina and abnormal condyles have not previously been reported.…”

Identifying the Growth Factors for Improving Neointestinal Regeneration in Rats through Transcriptome Analysis Using RNA-Seq Data

“…Although in week 12 “N”, growth factors related to regeneration, for instance, JAG2, PDGFC, PDGFB, and FBRS, have higher expression rates than in “A”, some suppressive factors like OSM or other more potent factors repress the regeneration events in “N”. In addition, in week 12, the expression level of KITLG – a stem cell factor [53] in “N” is similar to “A”, indicating that the regeneration event is terminated for a while. This could explain why the regeneration activity in week 12 “N” is suppressed.…”

The Interplay between Nevi and Melanoma Predisposition Unravels Nevi-Related and Nevi-Resistant Familial Melanoma

“…These studies reported single nucleotide polymorphisms (SNPs) on chromosomes 6 (mapping in the IRF4 gene), 9 (in the MTAP and DOCK8 genes and in the 9q31.2 region), 12 (in the KITLG gene), and 22 (in the PLA2G6 gene) as the most highly predictive of the number of nevi. IRF4 is a transcription factor implicated in melanocyte pigmentation and proliferation [ 25 ]; MTAP acts in polyamine metabolism [ 26 ]; DOCK8 regulates signal transduction [ 27 ]; KIT -ligand ( KITLG ) acts in different biological pathways, including melanocyte development and melanin synthesis [ 28 ]; and PLA2G6 has a crucial role in the regulation of membrane dynamics and homeostasis [ 29 ]. Thus, multiple pathways appear to be involved in the susceptibility to nevi, supporting a polygenic model of nevogenesis lacking high-penetrance nevus genes.…”