The generation of cortical projection neurons relies on the coordination of radial migration with branching. Here, we report that the multisubunit histone acetyltransferase Elongator complex, which contributes to transcript elongation, also regulates the maturation of projection neurons. Indeed, silencing of its scaffold (Elp1) or catalytic subunit (Elp3) cell-autonomously delays the migration and impairs the branching of projection neurons. Strikingly, neurons defective in Elongator show reduced levels of acetylated alpha-tubulin. Reduction of alpha-tubulin acetylation via expression of a nonacetylatable alpha-tubulin mutant leads to comparable defects in cortical neurons and suggests that alpha-tubulin is a target of Elp3. This is further supported by the demonstration that Elp3 promotes acetylation and counteracts HDAC6-mediated deacetylation of this substrate in vitro. Our results uncover alpha-tubulin as a target of the Elongator complex and suggest that a tight regulation of its acetylation underlies the maturation of cortical projection neurons.

Lysine acetylation is a post-translational modification that critically regulates gene transcription by targeting histones as well as a variety of transcription factors in the nucleus. More recent reports have also demonstrated that numerous proteins located outside the nucleus are also acetylated and that this modification has profound consequences on their functions. This review describes the latest findings on the substrates acetylated outside the nucleus and on the acetylases and deacetylates that catalyse these modifications. Protein acetylation is emerging as a major mechanism by which key proteins are regulated in many physiological processes such as migration, metabolism and aging as well as in pathological circumstances such as cancer and neurodegenerative disorders.

Background:Elongator is an acetylase complex that regulates cell migration. Results: DERP6 (ELP5) and C3ORF75 (ELP6) are characterized as Elongator subunits that control cell motility and tumorigenicity of melanoma cells. ELP5 ensures Elongator integrity by connecting ELP3 to ELP4. Conclusion: ELP5 and ELP6 are new players for migration and tumorigenicity of transformed cells. Significance: Elongator may be involved in both tumor initiation and progression.

b i o c h e m i c a l p h a r m a c o l o g y 7 5 ( 2 0 0 8 ) 2 1 2 2 -2 1 3Abbreviations: B2M, beta-2-microglobulin; BARD1, BRCA1-associated RING domain 1; BAX, BCL2-associated X protein; BTG2, B-cell translocation gene 2; CDK9, cyclin-dependent kinase 9; DMEM, Dulbecco's modified Eagle's medium; DUSP4, dual-specificity phosphatase 4; Elp, Elongator protein; EMEM, Eagle's modified essential medium; FACT, facilitates chromatin transcription; GFP, green fluorescent protein; HA, haemagglutinin; hELP1, human ELP1; IKAP, IKK-associated protein; IKK, inhibitor of kappa light chain gene enhancer in B cells kinase complex; NR2F2, nuclear receptor subfamily 2, group F, member 2; p21, cyclin-dependent kinase inhibitor 1A; PARP, poly (ADP-ribose) polymerase 1; PKIB, protein kinase, cAMP-dependent catalytic, inhibitor beta; RhoE/Rnd3, Rho family GTPase 3; SESN2, sestrin 2; SGK, serum-and glucocorticoid-induced protein kinase; shRNA, short hairpin RNA; TFIIF, general transcription factor IIF; TFIIH, general transcription factor IIH; TNFRSF10D, tumor necrosis factor receptor superfamily, member 10D.

135 NOUVELLES MAGAZINE2. Purpura DP. Dendritic spine « dysgenesis » and mental retardation 1.