Divergent Modulation of Neuronal Differentiation by Caspase-2 and -9
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AutorPistritto, Giuseppa; Papaleo, Veruska; Sánchez Medina, María del Pilar; Ceci, Claudia; Barbaccia, Maria Luisa
Public Library of Science (PLOS)
Adhesion moleculesApoptosisCell differentiationHistonesNeuronal differentiationNeuronsOrganism developmentProtein expression
Pistritto, G.; et al. Divergent Modulation of Neuronal Differentiation by Caspase-2 and -9. Plos One, 7(5): e36002 (2012). [http://hdl.handle.net/10481/30926]
PatrocinadorThis work was partially supported by a grant (n. 212413102008) from Regione Calabria-Italy and from the Research Fund of Tor Vergata University, Rome, Italy.
Human Ntera2/cl.D1 (NT2) cells treated with retinoic acid (RA) differentiate towards a well characterized neuronal phenotype sharing many features with human fetal neurons. In view of the emerging role of caspases in murine stem cell/neural precursor differentiation, caspases activity was evaluated during RA differentiation. Caspase-2, -3 and -9 activity was transiently and selectively increased in differentiating and non-apoptotic NT2-cells. SiRNA-mediated selective silencing of either caspase-2 (si-Casp2) or -9 (si-Casp9) was implemented in order to dissect the role of distinct caspases. The RA-induced expression of neuronal markers, i.e. neural cell adhesion molecule (NCAM), microtubule associated protein-2 (MAP2) and tyrosine hydroxylase (TH) mRNAs and proteins, was decreased in si-Casp9, but markedly increased in si-Casp2 cells. During RA-induced NT2 differentiation, the class III histone deacetylase Sirt1, a putative caspase substrate implicated in the regulation of the proneural bHLH MASH1 gene expression, was cleaved to a ~100 kDa fragment. Sirt1 cleavage was markedly reduced in si-Casp9 cells, even though caspase-3 was normally activated, but was not affected (still cleaved) in si-Casp2 cells, despite a marked reduction of caspase-3 activity. The expression of MASH1 mRNA was higher and occurred earlier in si-Casp2 cells, while was reduced at early time points during differentiation in si-Casp9 cells. Thus, caspase-2 and -9 may perform opposite functions during RA-induced NT2 neuronal differentiation. While caspase-9 activation is relevant for proper neuronal differentiation, likely through the fine tuning of Sirt1 function, caspase-2 activation appears to hinder the RA-induced neuronal differentiation of NT2 cells.