A15

RNA-binding proteins (RBPs) play key roles in the fate of mRNAs within a cell, e.g. the asymmetric segregation of mRNAs into specific subcellular compartments in polarized cells. This enables neuronal differentiation and synaptic function. In this context, the Kiebler lab has previously characterized two important RBPs, Staufen2 (Stau2) and Pumilio2 (Pum2) and their contribution to dendritic mRNA localization and local protein synthesis at the activated synapse.

In this new project, we aim to unravel the role of Stau2 and Pum2 in asymmetric mRNA distribution in neuronal stem cells, neuronal progenitors and mature neurons in the hippocampus. Furthermore, we plan to evaluate their influence to neuronal differentiation, maturation and functional integration into existing neural circuits. We are taking advantage of two new transgenic rat models that allow either tissue-specific, Cre-dependent or constitutive silencing of Stau2 (Stau2^KD), and gene-trap mice that are deficient for Stau2 (Stau2^GT), Pum2 (Pum2^GT) or both (Stau2^GT-Pum2^GT).

First, we will investigate the role of Stau2 and Pum2 in adult neurogenesis by (i) studying RBP-dependent asymmetric mRNA distribution in neuronal progenitors; (ii) determining the neurogenesis rate in WT vs. Stau2^GT or Pum2^GT adult hippocampus; and (iii) investigating learning-induced neurogenesis. Second, we will unravel the in vivo role of Stau2 and Pum2 in synaptic plasticity and therefore in learning and memory. Interestingly, the above-mentioned animal models, e.g. Stau2^KD and Stau2^GT both show deficits in hippocampal synaptic plasticity and in hippocampal spatial working memory, novelty detection and temporal association memory. We will investigate whether there are alterations in the asymmetric distribution of Stau2 mRNA targets encoding synaptic proteins, both in cultured Stau2^KD rat hippocampal neurons as well as in brain sections derived from Stau2^KD rats. Furthermore, we will study synaptic activity-dependent mRNA localization and translation of these Stau2 targets both in vitro and in vivo.

We are convinced that dissecting the molecular mechanisms of how Stau2 and Pum2 contribute to hippocampal neurogenesis, synaptic plasticity and working memory will advance our understanding of remarkably diverse cognitive and neurological symptoms both during healthy ageing as well as in many neurological diseases.