Interleukin-7 (IL-7) and IL-7 splice variants affect differentiation of human neural progenitor cells.
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-7 delta 5, delta 4 or delta 4/5 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 (P<0.01) defined by anti-beta (III)-tubulin and glial fibrillary acidic protein expression, with different degrees (IL-7c>delta 4/5>IL-7 delta 5); IL-7 delta 4 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 krüppel-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.
Moors
M
M
Group of Toxicology, Institut für Umweltmedizinische Forschung, Düsseldorf, Germany.
Vudattu
N K
NK
Abel
J
J
Krämer
U
U
Rane
L
L
Ulfig
N
N
Ceccatelli
S
S
Seyfert-Margolies
V
V
Fritsche
E
E
Maeurer
M J
MJ
D000328:Adult; D017398:Alternative Splicing / Q000502:physiology*; D001921:Brain / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D015851:Interleukin-7 / Q000096:biosynthesis*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism; D012322:RNA Precursors / Q000378:metabolism*; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*
C508605:IL7 protein, human; D015851:Interleukin-7; D012322:RNA Precursors