The role of the proto-oncogene Ski in cortical development

The proto-oncogene Ski is an evolutionary conserved protein associated with various cellular processes such as proliferation and differentiation as well as transformation and tumor progression. Ski has been found to interact with various factors such as transcription factors, hormone receptors and different members of transcriptional repressor complexes. Since all these results were obtained in cell lines under overexpression conditions, it is not known yet which interactions Ski is involved under physiological conditions.
Ski deficient mice show diverse developmental defects and are perinatal lethal. Even though recent progress has been made in identifying layer and subtype specific genes in the developing cortical plate, little is actually known about their function. In the present work, the endogenous protein Ski is shown to be a new fundamental factor in callosal neuron specification during brain development. In the absence of Ski, misspecified callosal projection neurons largely fail to form the corpus callosum and project instead to subcortical targets.
Ski interacts with the chromatin-remodelling factor Satb2 for transcriptional repression of the transcription factor Ctip2. Neither an interaction with Satb2 nor the regulation of Ctip2 by Ski has been reported yet. Here, for the first time an association of Ski with the NURD complex is shown. A proliferation defect and precocious differentiation in the early brain of Ski deficient mice are described. An altered proliferation of the intermediate progenitor population and a timing defect in neurogenesis of deep layer neurons of the cortical plate are also reported.
These findings demonstrate a central role for Ski in regulating transcriptional mechanisms of callosal neuron specification. They are of particular relevance in view of the essential role of accurate connectivity and identity of neuronal projections.