GDE2 regulates excitatory cortical neuronal identity by controlling the timing of cortical progenitor differentiation

The mammalian neocortex is a complex multilaminar structure consisting of specialized layer-specific neurons that form intricate networks with other areas of the nervous system. The generation of the cortical laminae follows a defined sequence, and the identity of the various neuronal populations is tightly related to their birthdate. During corticogenesis, early born neurons settle in deep cortical layers while late born neurons populate more superficial layers. Here we show that GDE2, a six-transmembrane protein expressed in the developing cortex throughout cortical neurogenesis, controls the tempo of cell-cycle exit of cortical progenitors thereby influencing the identity of excitatory cortical neurons. In the absence of GDE2, cortical progenitors fail to exit the cell-cycle on time, remain cycling and exit the cell-cycle en masse towards the end of the neurogenic period. These dynamic changes in cell-cycle progression lead to deficits in the number of deep layer neurons and robust increases in superficial neuronal numbers. Moreover, Gde2-/- cortices show elevated levels of Notch signaling early in corticogenesis, coincident with when progenitors fail to differentiate. These findings suggest that abnormal Notch activation retains cells in a proliferative phase for longer, biasing them to superficial fates. These observations define a key role for GDE2 in controlling cortical neuronal fates by regulating the timing of neurogenesis. Finally, we have observed that absence of GDE2 in the adult leads to neurodegenerative pathological and behavioral changes, suggesting that GDE2's function extends beyond the neurogenic period.