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The protooncogene Ski regulates the neuron-glia switch during development of the mammalian cerebral cortex.

Alice Grison 1 , Zahra Karimaddini 2, 3 , Jeremie Breda 3, 4 , Tanzila Mukhtar 1, , Marcelo Boareto 2, 3 , Katja Eschbach 2, , Christian Beisel 2, , Dagmar Iber 2, 3 , Erik van Nimwegen 3, 4 , Verdon Taylor 1 , and Suzana Atanasoski 1, 5 ✱ ,

Affiliations:

  • 1 Department of Biomedicine, University of Basel, Mattenstrasse 28, CH-4058 Basel, Switzerland.
  • 2 Department of Biosystems Science and Engineering, ETH Zürich, CH-4058 Basel, Switzerland.
  • 3 Swiss Institute of Bioinformatics (SIB), Mattenstrasse 26, CH-4058 Basel, Switzerland.
  • 4 Biozentrum, University of Basel, Klingelbergstrasse 50-70, CH-4056 Basel, Switzerland.
  • 5 Faculty of Medicine, University of Zürich, Zürich.

✱ Correspondence: suzana.atanasoski (at) uzh.ch (S.A)

The brain is the most complex organ in mammals and understanding the origin of this complexity is a major challenge for developmental biologists. Crucial to the size and morphology of the cortex is the timing and transition of neural stem cell (NSC) fate. An interesting candidate for modulating and fine tuning these processes is the transcriptional regulator Ski, a protooncogene expressed in cortical cells. Ski is involved in diverse cellular processes and epigenetic programs, and mice deficient in Ski exhibit complex central nervous system defects that resemble some of the features observed in patients with 1p36 deletion syndrome and Shprintzen–Goldberg syndrome. Here, we took advantage of in vivo transgenic labeling and next-generation sequencing to analyze the gene expression profiles of NSCs, basal progenitor (BP) cells, and newborn neurons (NBNs) from wildtype and Ski-deficient embryos throughout cortical development. We created a unique database that allowed us to identify and compare signaling pathways and transcriptional networks within each progenitor population in the presence and absence of Ski. We find that NSCs are the most affected cell population and uncover that mutant NCSs fail to switch to a gliogenic fate in time. We show that Ski functions in concert with the BMP signaling pathway to alter the cell differentiation fate of NSCs from neurons to glia, which is key to generating adequate numbers of specific cell types during corticogenesis. Thus, by combining genetic tools and bioinformatic analysis, our work not only deepens the knowledge of how Ski functions in the brain, but also provides an immense resource for studying neurodevelopmental disorders.

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