1. Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.
- Author
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Ghisi M, Corradin A, Basso K, Frasson C, Serafin V, Mukherjee S, Mussolin L, Ruggero K, Bonanno L, Guffanti A, De Bellis G, Gerosa G, Stellin G, D'Agostino DM, Basso G, Bronte V, Indraccolo S, Amadori A, and Zanovello P
- Subjects
- 3' Untranslated Regions, Adult, Apoptosis, Cell Line, Cell Line, Tumor, Cell Proliferation, Cells, Cultured, Child, Preschool, Gene Expression Profiling, Genes, Reporter, Humans, Infant, Infant, Newborn, MicroRNAs antagonists & inhibitors, MicroRNAs genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma metabolism, RNA, Messenger metabolism, Receptor, Notch3, Receptors, Notch antagonists & inhibitors, Receptors, Notch genetics, T-Lymphocyte Subsets cytology, T-Lymphocyte Subsets metabolism, Thymus Gland cytology, Thymus Gland metabolism, Cell Differentiation, Gene Expression Regulation, MicroRNAs metabolism, Receptors, Notch metabolism, T-Lymphocytes cytology, T-Lymphocytes metabolism
- Abstract
Ontogenesis of T cells in the thymus is a complex process whose molecular control is poorly understood. The present study investigated microRNAs involved in human thymocyte differentiation by comparing the microRNA expression profiles of thymocytes at the double-positive, single-positive CD4(+) and single-positive CD8(+) maturation stages. Microarray analysis showed that each thymocyte population displays a distinct microRNA expression profile that reflects their developmental relationships. Moreover, analysis of small-RNA libraries generated from human unsorted and double-positive thymocytes and from mature peripheral CD4(+) and CD8(+) T lymphocytes, together with the microarray data, indicated a trend toward up-regulation of microRNA expression during T-cell maturation after the double-positive stage and revealed a group of microRNAs regulated during normal T-cell development, including miR-150, which is strongly up-regulated as maturation progresses. We showed that miR-150 targets NOTCH3, a member of the Notch receptor family that plays important roles both in T-cell differentiation and leukemogenesis. Forced expression of miR-150 reduces NOTCH3 levels in T-cell lines and has adverse effects on their proliferation and survival. Overall, these findings suggest that control of the Notch pathway through miR-150 may have an important impact on T-cell development and physiology.
- Published
- 2011
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