Biology subjects

Gaber, Z.

Publications and source records attributed to Gaber, Z..

3 recordsLinked to original sources

bioRxiv2020

Progressive changes in hippocampal stem cell properties ensure lifelong neurogenesis

Neural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilise during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this reduction in stem cell depletion rate is the result of multiple coordinated changes in stem cell behaviour. In particular, while active neural stem cells divide only once or twice before differentiating rapidly in juveniles, they increasingly return to a resting state of shallow quiescence and progress through additional self-renewing divisions in adulthood. Single-cell transcriptomic, mathematical modelling and label-retention analyses indicate that resting cells have a higher activation rate and greater contribution to neurogenesis than dormant cells, which have not left quiescence. These progressive changes in stem cell behaviour result from reduced expression of the pro-activation protein ASCL1 due to increased post-translational degradation. These mechanisms help reconcile current contradictory models of hippocampal NSC dynamics and may contribute to the different rates of decline of hippocampal neurogenesis in mammalian species including humans.

developmental 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↗

bioRxiv2017

Olig2 and Hes regulatory dynamics during motor neuron differentiation revealed by single cell transcriptomics

During tissue development, multipotent progenitors differentiate into specific cell types in characteristic spatial and temporal patterns. We address the mechanism linking progenitor identity and differentiation rate in the neural tube, where motor neuron (MN) progenitors differentiate more rapidly than other progenitors. Using single cell transcriptomics, we define the transcriptional changes associated with the transition of neural progenitors into MNs. Reconstruction of gene expression dynamics from these data indicate a pivotal role for the MN determinant Olig2 just prior to MN differentiation. Olig2 represses expression of the Notch signaling pathway effectors Hes1 and Hes5. Olig2 repression of Hes5 appears to be direct, via a conserved regulatory element within the Hes5 locus that restricts expression from MN progenitors. These findings reveal a tight coupling between the regulatory networks that control patterning and neuronal differentiation, and demonstrate how Olig2 acts as the developmental pacemaker coordinating the spatial and temporal pattern of MN generation.

developmental biology↗