The neuronal fate determinants SOX4/11 control mitotic fidelity of adult hippocampal precursor cells

In adult hippocampal neurogenesis, fast dividing intermediate progenitor cells (IPCs) ensure the production of a larger number of neurons from a limited pool of slow dividing radial-glia-like neural stem cells. Here, we demonstrate that the neuronal fate determining and lineage-specific transcription factors SOX4 and SOX11 are essential to faithfully execute mitosis in IPCs. In vivo, combined deletion of SOX4 and SOX11 results in death of IPCs and abolishes the generation of new neurons. In vitro analyses of SOX4/11-deficient precursors revealed mitosis defects including chromosome segregation errors, centrosomal errors and cytokinesis defects. SOX4/11-deficient precursors frequently featured micronuclei and DNA bridges and showed a pro-inflammatory signaling profile, suggesting the induction of death by mitotic catastrophe. Importantly, analysis of the developing mouse spinal cord and of human pluripotent stem cell-derived brain organoids indicate that SOXC transcription factors are essential for mitotic fidelity of neural precursor cells across ontogeny and species. The data raise the interesting possibility that mitotic programs in precursor cells are controlled in a lineage-specific manner.