title: Novel Interaction of Class IIb Histone Deacetylase 6 (HDAC6) with Class IIa HDAC9 Controls Gonadotropin Releasing Hormone (GnRH) Neuronal Cell Survival and Movement.
abstract: 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 with 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 up-regulated at the mRNA and protein levels, and HDAC6 catalytic activity was significantly increased in GT1-7 compared with NLT cells. HDAC9 interacted with HDAC6 through its second catalytic domain. Silencing of HDAC6, HDAC9, or both, in GT1-7 cells augmented apoptosis compared with 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 α-tubulin. Inhibition of HDAC6 and HDAC9 together resulted in an additive effect to increase cell movement but did not alter the acetylation of αtubulin. Together, these studies identify a novel interaction of Class IIa HDAC9 with Class IIb HDAC6 to modulate cell movement and survival in GnRH neurons.
authors: From the Division of Endocrinology, Metabolism, and Diabetes and.
authors: Smita
authors: S
authors: Salian-Mehta
authors: From the Division of Endocrinology, Metabolism, and Diabetes and.
authors: Mei
authors: M
authors: Xu
authors: Division of Cardiology, University of Colorado School of Medicine, Aurora, Colorado 80045.
authors: Timothy A
authors: TA
authors: McKinsey
authors: Department of Biomedical Sciences, Colorado State University, Fort Collins, Colorado 80523.
authors: Stuart
authors: S
authors: Tobet
authors: From the Division of Endocrinology, Metabolism, and Diabetes and Research Service Veterans Affairs Medical Center, Denver, Colorado 80220, and margaret.wierman@ucdenver.edu.
authors: Margaret E
authors: ME
authors: Wierman
mesh_terms: D000818:Animals; D017209:Apoptosis; D020134:Catalytic Domain; D002460:Cell Line; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D014162:Transfection; D014404:Tubulin / Q000378:metabolism
chemical_list: D012097:Repressor Proteins; D014404:Tubulin; D007987:Gonadotropin-Releasing Hormone; C499033:Hdac6 protein, mouse; C486545:Hdac9 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases
keywords: GnRH; Hdac9; apoptosis; cell migration; histone deacetylase (HDAC); histone deacetylase 6 (HDAC6); hypothalamus; movement; survival