Dagmar iber 3,4 , christian Beisel 5 , erik van nimwegen 2 & Verdon taylor 1* Neural stem cells (NSCs) generate neurons of the cerebral cortex with distinct morphologies and functions. How specific neuron production, differentiation and migration are orchestrated is unclear. Hippo signaling regulates gene expression through Tead transcription factors (TFs). We show that Hippo transcriptional coactivators Yap1/Taz and the Teads have distinct functions during cortical development. Yap1/Taz promote NSC maintenance and Satb2 + neuron production at the expense of Tbr1 + neuron generation. However, Teads have moderate effects on NSC maintenance and do not affect Satb2 + neuron differentiation. Conversely, whereas Tead2 blocks Tbr1 + neuron formation, Tead1 and Tead3 promote this early fate. In addition, we found that Hippo effectors regulate neuronal migration to the cortical plate (CP) in a reciprocal fashion, that ApoE, Dab2 and Cyr61 are Tead targets, and these contribute to neuronal fate determination and migration. Our results indicate that multifaceted Hippo signaling is pivotal in different aspects of cortical development. NSCs of the developing cerebral cortex form the ventricular zone (VZ) lining the lumen of the neural tube 1-5. NSCs in the dorsal anterior forebrain are the major source of the projection neurons of the cerebral cortex 4,5. The mechanisms controlling the patterning and cell fate specification of these stem cells during early brain development are not clearly understood. Although various signaling pathways including Notch, Wnt, Shh, FGFs, TGF-β, Retinoic acid, Reelin and Hippo are known to regulate NSC proliferation and to control fate decisions, neurogenesis, and gliogenesis; the crosstalk between the different signaling pathways and the integration of these signals on target genes governing complex cell fate choices is unclear 1-3. Hippo signaling is evolutionarily conserved and a regulator of organ size control and tissue homeostasis 6-9. The pathway is regulated by numerous stimuli including G-protein coupled receptor signaling, mechanical stress, cellular energy status, cell-cell contact and cell-extra-cellular matrix interactions 6-8. Hippo signaling employs a cascade of phosphorylation steps mediated by the kinases Mst1/2 and Lats1/2 8-10. Lats1/2 phosphorylate the transcriptional coregulators Yap1 and Taz to promote cytoplasmic retention and subsequent degradation 6-8. When Hippo signaling is inactive, Yap1/Taz translocate to the nucleus and form multiple complexes with different DNA binding partners including TEADs, SMADs, and Runx TFs (Fig. S1a) 8-10. The Teads are major regulators of Hippo target genes in many systems including cancer 8,11,12. Fat4 and Dchs are receptor and ligand, respectively, of the Hippo pathway in embryonic NSCs. Knockdown of Fat4 results in increased proliferation in the developing nervous system and reduction of neuronal differentiation 13,14. Mutations in FAT4 and DCHS cause Van Maldergem syndrome in humans, an autosomal-recessive disorder characterized by in...

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article.

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