Gde2 regulates cortical neuronal identity by controlling the timing of cortical progenitor differentiation

Abstract

The mammalian cortex is a multilaminar structure consisting of specialized layer-specific neurons that form complex circuits throughout the brain and spinal cord. These neurons are generated in a defined sequence dictated by their birthdate such that early-born neurons settle in deep cortical layers whereas late-born neurons populate more superficial layers. Cortical neuronal birthdate is partly controlled by an intrinsic clock-type mechanism; however, the role of extrinsic factors in the temporal control of cell-cycle exit is less clear. Here, we show that Gde2, a six-transmembrane protein that induces spinal neuronal differentiation, is expressed in the developing cortex throughout cortical neurogenesis. In the absence of Gde2, cortical progenitors fail to exit the cell cycle on time, remain cycling, accumulate and exit the cell cycle en masse towards the end of the neurogenic period. These dynamic changes in cell-cycle progression cause deficits and delays in deep-layer neuronal differentiation and robust increases in superficial neuronal numbers. Gde2−/− cortices show elevated levels of Notch signaling coincident with when progenitors fail to differentiate, suggesting that abnormal Notch activation retains cells in a proliferative phase that biases them to superficial fates. However, no change in Notch signaling is observed at the time of increased cell-cycle exit. These observations define a key role for Gde2 in controlling cortical neuronal fates by regulating the timing of neurogenesis, and show that loss of Gde2 uncovers additional mechanisms that trigger remaining neuronal progenitors to differentiate at the end of the neurogenic period.

Neural progenitor cells orchestrate microglia migration and positioning into the developing cortex

“…Since it has been previously shown that the inhibition of the canonical Notch signalling in the developing forebrain might cause the premature differentiation of RG into neurons [22][23][24][25] , we then asked whether the blockage of Delta/Notch signalling into the developing cortex could lead to an overproduction of BP that, in turn, might alter microglia number and/or positioning within the cerebral cortex. Thus, to induce blockage of Notch signalling in cortical RG, we electroporated E14.5 forebrains with a plasmid carrying the dominant-negative form of Mastermind-like 1 gene (dnMAMl) 26 .…”

Activated retinoid receptors are required for the migration and fate maintenance of subsets of cortical neurons

“…In utero electroporation Procedures were performed as described (Rodriguez et al, 2012). Briefly, timed pregnant dams were anesthetized by intraperitoneal (i.p.)…”

“…Neuronal fate is determined by the timing of progenitor cell cycle exit, and the competence of progenitors to generate deep-layer neurons decreases over time (Luskin et al, 1988;McConnell and Kaznowski, 1991;Desai and McConnell, 2000;Frantz and McConnell, 1996). In vitro studies reveal that cortical neurons differentiate in an ordered fashion, with deep-layer neurons born first followed by more superficial ones, consistent with intrinsic clock-like mechanisms of differentiation (Gaspard et al, 2008;Qian et al, 2000;Shen et al, 2006); however, extrinsic factors can influence the time of cell cycle exit and are thus important regulators of cortical neuronal diversity (Mizutani and Saito, 2005;Rodriguez et al, 2012). Nevertheless, the control of progenitor cell cycle exit is unlikely to be the sole factor that defines the fates of cortical neurons.…”

Central nervous system-specific knockout of Brg1 causes growth retardation and neuronal degeneration

“…Ko of Brg1 seemed to cause an increase in the number of astrocytes, which may be associated with neuronal degeneration in the cortex. At E12.5, neuron progenitors are already differentiated from neural stem cells and enter the path of neuron differentiation, and astrocytes continue to differentiate throughout development (Rodriguez et al, 2012). Brg1 is required for astrocyte differentiation (Matsumoto et al, 2006).…”