Abstract
Neural progenitors in the embryonic neocortex must be tightly regulated in order to generate the correct number and projection neuron subtypes necessary for the formation of functional neocortical circuits. In this study, we show that the intracellular protein Suppressor of Fused (Sufu) regulates the proliferation of intermediate progenitor (IP) cells at later stages of corticogenesis to affect the number of Cux1+ upper layer neurons in the postnatal neocortex. This correlates with abnormal levels of the repressor form of Gli3 (Gli3R) and the ectopic expression of Patched 1 (Ptch1), a Sonic Hedgehog (Shh) target gene. These studies reveal that the canonical role of Sufu as an inhibitor of Shh signaling is conserved at later stages of corticogenesis and that Sufu plays a crucial role in regulating neuronal number by controlling the cell cycle dynamics of IP cells in the embryonic neocortex.
Highlights
The generation of molecularly diverse glutamatergic projection neurons in the adult mammalian neocortex is dynamically regulated by spatial and temporal events during embryonic cortical development
All glutamatergic projection neurons originate from neural progenitors in the ventricular (VZ) and subventricular zone (SVZ), which are derived from multipotent radial glial (RG)
intermediate progenitor (IP) cells that populate the SVZ at later stages of corticogenesis will undergo one or more symmetric divisions before terminally differentiating to produce a pair of neurons that will largely populate the upper layers of the neocortex [4]
Summary
The generation of molecularly diverse glutamatergic projection neurons in the adult mammalian neocortex is dynamically regulated by spatial and temporal events during embryonic cortical development. Suppressor of Fused (Sufu) is a critical antagonist of Shh signaling that influences patterning, specification, differentiation, and migration of neural progenitors and their progenies in the developing central nervous system [6,9,10,11] Sufu exerts this role by directly acting on Gli transcription factors downstream of the Shh signaling cascade via control of their stability, degradation, and the formation of Gli repressors [11,12,13,14]. Loss of Sufu deregulates the proliferation program of basally dividing cortical progenitors resulting in an increase in the number of upper layer neurons in the postnatal neocortex These observations correlate with an increase in Shh activity, in part due to an imbalance between the full-length Gli activator (Gli3FL) and the cleaved Gli3R repressor (Gli3R). These studies elucidate an important role for Sufu in regulating Shh signaling activity in late corticogenesis
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