Novel Interaction of Class IIb Histone Deacetylase (HDAC) 6 with Class IIa HDAC9 Controls GnRH Neuronal Cell Survival and Movement [Developmental Biology]

April 14th, 2015 by Salian-Mehta, S., Xu, M., McKinsey, T. A., Tobet, S., Wierman, M. E.

The impact of histone deacetylases (HDACs) in the control of Gonadotropin releasing hormone (GnRH) neuronal development is unknown. We identified an increase in many HDACs in GT1-7(differentiated) compared to NLT (undifferentiated) GnRH neuronal cell lines. Increased HDAC9 mRNA and protein, and specific deacetylase activity in GT1-7 cells suggested a functional role. Introduction of HDAC9 in NLT cells protected from serum withdrawal induced apoptosis and impaired basal neuronal cell movement. Conversely, silencing of endogenous HDAC9 in GT1-7 cells increased apoptosis and cell movement. Comparison of WT and mutant HDAC9 constructs demonstrated that the HDAC9 pro-survival effects required combined cytoplasmic and nuclear localization, whereas the effects on cell-movement required a cytoplasmic site of action. Co-immunoprecipitation demonstrated a novel interaction of HDAC9 selectively with the Class IIb HDAC6. HDAC6 was also upregulated at the mRNA and protein levels and HDAC6 catalytic activity was significantly increased in GT1-7 compared to NLT cells. HDAC9 interacted with HDAC6 through its second catalytic domain. Silencing of HDAC6, HDAC9, or both, in GT1-7 cells augmented apoptosis compared to controls.HDAC6 and 9 had additive effects to promote cell survival via modulating the BAX/BCL2 pathway. Silencing of HDAC6 resulted in an activation of movement of GT1-7 cells with induction in acetylation of ╬▒TUBULIN. Inhibition of HDAC6 and HDAC9 together resulted in an additive effect to increase cell movement, but did not alter the acetylation of ╬▒TUBULIN. Together, these studies identify a novel interaction of Class IIa HDAC9 with Class IIb HDAC6 to modulate cell movement and survival in GnRH neurons.
  • Posted in Journal of Biological Chemistry, Publications
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