Notch directs telencephalic development and neuron fate determination by regulating miRNA levels

The central nervous system (CNS) contains myriads of different types of
cells produced from multipotent neural progenitors through multiple rounds
of cell divisions. Neural progenitors acquire distinct cell identities
depending on their spatial position, but they are also influenced by
temporal cues to give rise to different cell populations over time. For
instance, the progenitors of the cerebral neocortex generate different
populations of excitatory projection neurons following a well-known
sequence that is conserved across species. The Notch signaling pathway
plays crucial roles in CNS development, including regulating the balance
between proliferation and differentiation and fate acquisition. However,
the molecular mechanisms by which Notch impacts progenitor fate decisions
and telencephalic patterning have not been fully resolved. Here, we show
that Notch signaling is essential for neocortical and hippocampal
morphogenesis as well as for the development of the corpus callosum and
the choroid plexus. In the neocortex, Notch regulates neural progenitor
cell cycle dynamics, neurogenesis, and the laminar cytoarchitecture. Our
data also indicate that Notch controls projection neuron fate
determination through the regulation of two microRNA (miRNA) clusters that
include let-7, miR-99a/100, and miR-125b. The expression of competitive
inhibitors of these miRNAs rescues the effects of Notch gain-of-function
in vivo. Our findings collectively suggest that balanced Notch signaling
is crucial for telencephalic development and that the interplay between
Notch and miRNAs is critical to control neocortical progenitor behaviors
and neuron cell fate decisions.