FAN

Defining the functions of Elongator in adult brain neurogenesis

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 Obiettivo del progetto (Objective)

'The olfactory bulb (OB) is one of the few structures in the adult forebrain in which there is a continuous supply of newborn neurons. Neuronal precursors are generated in the subventricular zone (SVZ) and follow an intricate migration path before reaching their final position in the OB. Familial dysautonomia is a neurodegenerative disorder that result from the impairment of Elongator activity. Elongator is a six unit complex assembled by its scaffold protein Elp1. The host laboratory has recently shown that the catalytic activity of this complex underlies radial migration and branching of cortical projection neurons by promoting the acetylation of α-tubulin. In the adult brain, the stem/neural progenitor express Elongator subunits and Elp1 level expression increases dramatically after treatment that promotes neurogenesis. The overall goal of the current project is to understand the functions of Elongator in adult brain neurogenesis. I propose: - To analyze the expression pattern of Elongator in adult SVZ. - To dissect the role of Elongator on neuroblasts migration within the rostral migratory stream (rostral migration) and the OB (radial migration). - To define the role of Elongator on interneuron differentiation in the OB. - To characterize new cytoplasmic targets of Elongator that promote adult neurogenesis.'

Introduzione (Teaser)

The adult brain retains stem/progenitor cells in the several zones they support neurogenesis throughout life. Understanding the molecular pathways that drive neurogenesis in adult brain is essential for replacement therapy after brain injury.

Descrizione progetto (Article)

Elongator is a multiprotein complex composed of 6 subunits (Elp1-6), which is expressed both in the nucleus and cytoplasm where its Elp3 acts as enzyme modificator. In the nucleus, it promotes transcriptional elongation and paternal genome demethylation, and in the cytoplasm, it contributes to exocytosis and tRNA modifications. EU funded 'Defining the functions of Elongator in adult brain neurogenesis' (FAN) project to investigate whether elongator contributes to neurogenesis in the adult brain and to characterize its acetylation targets.

Firstly, researchers demonstrated expression of the Elp subunits in micro-dissected postnatal mouse brain zones which retain stem cells. They also found that knockout Flp3 animals die before postnatal day 23. The size of the brain and, in particular, the thickness of the cortical plate was reduced upon Elp3 deletion, and knockout animals were hydrocephales.

Epithelia like cells involved in the production of cerebrospinal fluid, ependymal cells, are polarized through a multi-step process by primary cilia in radial glia and then refined by motile cilia in ependymal cells. Researchers showed that both polarities were impaired upon Elp3 deletion.

Finally they compared acetylome from Elp3 knockout and WT cortices in global analysis approach to indentifiy new proteins acetylated by Elp3. Among the candidates they found CEP290, a protein which mutations have been implicated in many autosomal disorders including early-onset retinal degeneration.

In conclusion, this study demonstrated for the first time the involvement of Elongator complex in ciliogenesis. Results of the project also pointed to a broader function of Elongator in different ciliated organs.