Modulating epigenetic mechanisms: the diverse functions of Ski during cortical development

In the developing forebrain, neural stem and progenitor cells generate a large variety of neurons with specific functions in the mature cortex. A central issue is to understand the roles of transcriptional networks and regulatory pathways that control these complex developmental processes. The proto-oncogene Ski is a transcriptional regulator linked to the human 1p36 deletion syndrome, which involves a set of phenotypes including nervous system defects. Ski shows a dynamic expression pattern during cortical development and, accordingly, the phenotype of Ski-deficient cortices is complex, involving altered cell cycle characteristics of neural progenitors, disturbed timing of neurogenesis and mis-specification of projection neurons. Ski is likely to play a role in various pathways by virtue of its ability to interact with a range of signaling molecules, thereby modulating transcriptional activity of corresponding target genes. Ski regulates proliferation and differentiation of various cell types, and more recent data from my laboratory demonstrates that Ski is also involved in the specification of cortical projection neurons. This Point-of-View elucidates the role of Ski as an essential linker between sequence-specific transcription factors and non-DNA binding cofactors with chromatin modifying activities. In particular, it puts forward the hypothesis that the diverse functions of Ski as a co-repressor might be related to its association with distinct HDAC-complexes.