Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells

Abstract

Alternative splicing of pre-mRNA increases proteomic diversity, a crucial mechanism in defining tissue identity. We demonstrate differentially spliced interleukin (IL)-7 in distinct anatomic areas in the adult, in developing human brains and in normal human neuronal progenitor (NHNP) cells. IL-7c (c, the canonical form spanning all six exons) or its variants IL-7d5, d4 or d4/5 were cloned and expressed as recombinant proteins. IL-7 and splice variants were able to shift the differentiation of NHNP cells as compared with the diluent control (Po0.01) defined by anti-b (III)-tubulin and glial fibrillary acidic protein expression, with different degrees (IL-7c4d4/54IL-7d5); IL-7d4 exhibited a significantly weaker potency. Differentiation was confirmed by transcriptome analysis of IL-7c-stimulated neural NHNP cells, resulting in 58 differentially expressed genes; some of these are involved in neural differentiation, for example, the developmentally regulated transcription factor krü ppel-like factor 12, musashi 2, a translational regulator of cell fate or the sonic hedgehog receptor patch 1. This suggests that IL-7 influences neural development at a molecular level by participating in human brain architecture through glia cell formation: a paradigm that alternative splicing in cytokines, for example, for IL-7, has a physiological role in human organ development and progenitor cell differentiation.

Increased (6 exon) interleukin-7 production after M. tuberculosis infection and soluble interleukin-7 receptor expression in lung tissue

“…7 This IL-7 isoform acts as an IL-7 agonist in promoting immune cell survival and differentiation of human thymocytes, and it also drives differentiation of human neuronal stem cells. 7,10 More recently, the IL-7R has been demonstrated to be alternatively spliced associated with different haplotypes that affect gene regulation and potentially RNA splicing 8,11 _ENREF_9. A particular haplotype has been associated with an increased risk of developing multiple sclerosis.…”

“…16 The IL-7R is expressed by a variety of immune 17,18 and non-immune cells, 7,10 either along with the common cytokine g-chain 19 or the receptor for thymic stromal lymphopoietin on dendritic cells. 20 The soluble form of the IL-7R blocks IL-7 activity.…”

Diverse Interleukin-7 mRNA Transcripts in Chinese Tree Shrew (Tupaia belangeri chinensis)

“…IL7 is produced by stromal cells in bone marrow and thymus [8], [9] as well as other types of cell, such as keratinocytes [10], hepatocytes [11], and epithelial cells [12]. Besides its pleiotropic role in the immune system, IL7 has been reported as a regulator of the development of central nervous system [13] and myogenesis and skeletal muscle cell migration [14].…”

Reference compounds for alternative test methods to indicate developmental neurotoxicity (DNT) potential of chemicals: Example lists and criteria for their selection and use_suppl

“…For each compound, the original literature documenting the effect on the targeted endpoint is indicated. 1 Zimmer et al, 2011b;2 Krug et al, 2013b;3 Balmer et al, 2012;4 Moors et al, 2009;5 Moors et al, 2010;6 Zimmer et al, 2011a;7 Zimmer et al, 2012;8 Moors et al, 2007;9 Gassmann et al, 2010;10 Tegenge et al, 2011;11 Mundy et al, 2010;12 Culbreth et al, 2012;13 Breier et al, 2008;14 Harrill et al, 2011a;15 Harrill et al, 2011b;16 Robinette et al, 2011;17 Hogberg and Bal-Price, 2011;18 Radio et al, 2008;19 Radio et al, 2010;20 Stiegler et al, 2011;21 Parran et al, 2001;22 Harrill et al, 2010;23 Mandell and Banker, 1998;24 Schreiber et al, 2010;25 tools" (Kadereit et al, 2012) would have a high probability of a positive effect within the context of a test system for a specific system's endpoint. However, knowledge of the "mechanism" of a chemical is not a prerequisite for identifying an endpoint-specific control if there is sufficient evidence showing selective effects on an endpoint within a test system.…”