Claudia Mahlke

Activity-dependent gene expression is central for sculpting neuronal connectivity in the brain. Despite the importance for synaptic plasticity, a comprehensive analysis of the temporal changes in the transcriptomic response to neuronal activity is lacking. In a genome wide survey we identified genes that were induced at 1, 4, 8, or 24 hours following neuronal activity in the hippocampus. According to their distinct expression kinetics we assigned these genes to five clusters, each containing approximately 200 genes. Using in situ hybridizations the regulated expression of 24 genes was validated. Apart from known activity-dependent genes our study reveals a large number of unknown induced genes with distinct expression kinetics. Among these we identified several genes with complex temporal expression patterns. Furthermore, our study provides examples for activity-induced exon switching in the coding region of genes and activity-induced alternative splicing of the 39-UTR. One example is Zwint. In contrast to the constitutively expressed variant, the induced Zwint transcript harbors multiple regulatory elements in the 39-UTR. Taken together, our study provides a comprehensive analysis of the transcriptomic response to neuronal activity and sheds new light on expression kinetics and alternative splicing events.

SorCS3 is a member of the Vps10p-D receptor family. These type I transmembrane proteins are regarded as sorting receptors, and some family members modulate signal transduction pathways by acting as co-receptors. SorCS3 binds the nerve growth factor (NGF) and platelet-derived growth factor (PDGF-BB), but the functional implications of these interactions are poorly understood. Here we demonstrate that SorCS3 is almost exclusively expressed in the nervous system and is localized to vesicular structures. By using in situ hybridization, we analyze SorCS3 dynamic expression during embryonic and postnatal development and compare the expression pattern with those of the homologous genes SorCS1 and SorCS2. SorCS3 transcripts are widely distributed in the nervous system but are absent from the embryonic cerebral cortex. SorCS3 expression marks thalamic nuclei at embryonic and early postnatal stages. However, during postnatal development and in the adult, a switch in the localization of SorCS3 transcripts was observed. At these stages forebrain structures, such as the hippocampus and the cerebral cortex, show most prominent expression. The developmental expression pattern of SorCS3 is in accordance with the proposed function as a receptor for growth factors or morphogenic signals. On the cellular level, we demonstrate that the SorCS3 cytoplasmic domain targets receptors to the Golgi apparatus, vesicular structures, and the cell surface. In neurons, receptors are localized to vesicles in the soma and dendrites. Moreover, we show that the SorCS3 cytoplasmic domain conveys internalization through canonical endocytic motifs in an adaptor protein 2 (AP-2)-dependent way. This is in agreement with a proposed function as a neuronal sorting receptor.