Biology subjects

Guillemot, F.

Publications and source records attributed to Guillemot, F..

3 recordsLinked to original sources

bioRxiv2018

Temporal control of cortico-thalamic neuron specification by regulation of Neurogenin activity and Polycomb repressive complexes

Neural progenitor cells (NPCs) in the embryonic mammalian neocortex generate different neuronal subtypes sequentially. A long-standing hypothesis to account for this temporal fate specification process is that NPCs change their differentiation potential over time. However, the molecular mechanisms underlying these temporal changes in NPC properties are poorly understood. Here we show that Neurogenin1 and Neurogenin2 (Neurog1/2), two proneural transcription factors expressed in NPCs throughout cortical neurogenesis, specify the identity of one of the first cortical neuron subtypes generated, layer 6 cortico-thalamic neurons (CTNs). We found that Neurog1/2 specify the CTN fate through regulation of the cortical fate determinants Fezf2 and Foxp2 and that this Neurog-induced programme becomes inactive after the period of CTN production. Two independent mechanisms contribute to the arrest of CTN neuron generation at the end of layer 6 neurogenesis, including a reduction in the transcriptional activity of Neurog1/2 and the deposition of epigenetic repressive modifications mediated by Polycomb repressive complexes at the Foxp2 gene. Therefore, the duration of production of a cortical neuron subtype is controlled by multiple locking mechanisms involving both transcriptional and epigenetic processes.

neuroscience↗

bioRxiv2018

Id4 eliminates the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells

Quiescence is essential for the long-term maintenance of adult stem cells and tissue homeostasis. However, how stem cells maintain quiescence is still poorly understood. Here we show that stem cells in the dentate gyrus of the adult hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activation state. We found that the inhibitor of DNA binding protein Id4 suppresses Ascl1 activity in neural stem cell cultures. Id4 sequesters Ascl1 heterodimerisation partner E47, promoting Ascl1 protein degradation and neural stem cell quiescence. Accordingly, elimination of Id4 from stem cells in the adult hippocampus results in abnormal accumulation of Ascl1 protein and premature stem cell activation. We also found that multiple signalling pathways converge on the regulation of Id4 to reduce the activity of hippocampal stem cells. Id4 therefore maintains quiescence of adult neural stem cells, in sharp contrast with its role of promoting the proliferation of embryonic neural progenitors.

cell biology↗

bioRxiv2018

Bcl6 promotes neurogenic conversion through transcriptional repression of multiple self-renewal-promoting extrinsic pathways.

During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here we combine whole genome transcriptional and epigenetic analyses with in vivo functional studies and show that Bcl6, a transcriptional repressor known to promote neurogenesis, acts as a key driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 acts through both generic and pathway-specific mechanisms. Our data identify a molecular logic by which a single cell-intrinsic factor ensures robustness of neural cell fate transition by decreasing responsiveness to the extrinsic pathways that favor self-renewal.

neuroscience↗