Imbalanced neurogenesis and gliogenesis in the developing neocortex of mice lacking the proteoglycan Tsukushi

: Development of the mammalian neocortex relies on a tightly controlled schedule, wherein cortical progenitors initially expand by symmetric divisions, then sequentially generate neurons of the deep and superficial cortical layers by asymmetric divisions, and finally give rise to glial cell populations. This sequence of events is orchestrated by a complex network of transcriptional regulators and extracellular signals ensuring a proper balance between cortical expansion and the production of neurons and glia. Although the transcription factors governing progenitor self-renewal, neurogenesis and gliogenesis are largely known, the extracellular cues modulating these processes are less understood. Here, we investigate neocortical development in mice lacking the proteoglycan Tsukushi (TSK), which bear hydrocephalus with neurological deficits. We show that TSK is expressed in the cortical plate, where differentiating neurons and glia give rise to the mature cortex. By single-cell transcriptomics and validation of key molecular markers at the mRNA and protein levels, we report an increased astrogliogenesis at the expense of neurogenesis in TSK-deficient neocortex. These results unveil TSK requirement to balance cortical neurogenesis and gliogenesis and support models linking alterations in neuro-gliogenesis to hydrocephalus.