First name
Jacopo
Last name
Sgualdino
Year of Study
Thesis Title
Role of the Histone Demethylase Jmjd3 in cortical development and neural differentiation
Thesis Abstract
Jmjd3 is a H3K27 demethylase that is required for the neural commitment of ESCs and controls the expression of key drivers and markers of neurulation through the demethylation of H3K27me3. Previous work from our lab has demonstrated that loss of Jmjd3 in mouse embryos causes a complex neurodevelopmental phenotype that results in perinatal death, due to respiratory failure resulting from the lack of a small network of neurons that is responsible for respiratory rhythm generation. Rescue experiments performed with catalytically active or inactive Jmjd3 have demonstrated that its demethylase activity is necessary for developing and maintaining the embryonic respiratory neuronal network.
To investigate the effect of Jmjd3 loss on neocortical development, we analyzed Jmjd3 KO embryonic brains at different developmental stages using markers for stem cells and differentiated neurons. We found that loss of Jmjd3 causes an increase in the number of ventricular zone (VZ) neural precursor cells (NPCs) and a reduction in the cortical neuronal production, and that Jmjd3 KO VZ NPCs display a higher rate of cell cycle re-‐entry together with a longer cell cycle.
A detailed molecular characterization at the transcriptional level by RNA sequencing revealed that the phenotype that we observed both in vivo and in vitro in Jmjd3 KO NPCs is linked to supraphysiological activation of the Wnt/B-‐ catenin and Notch pathways, two known regulators of the choice between self-‐ renewal and differentiation in the VZ NPCs of the developing brains, whose upregulation has been shown to correlate with an increased proliferative potential and hampered neuronal differentiation.
To investigate the effect of Jmjd3 loss on neocortical development, we analyzed Jmjd3 KO embryonic brains at different developmental stages using markers for stem cells and differentiated neurons. We found that loss of Jmjd3 causes an increase in the number of ventricular zone (VZ) neural precursor cells (NPCs) and a reduction in the cortical neuronal production, and that Jmjd3 KO VZ NPCs display a higher rate of cell cycle re-‐entry together with a longer cell cycle.
A detailed molecular characterization at the transcriptional level by RNA sequencing revealed that the phenotype that we observed both in vivo and in vitro in Jmjd3 KO NPCs is linked to supraphysiological activation of the Wnt/B-‐ catenin and Notch pathways, two known regulators of the choice between self-‐ renewal and differentiation in the VZ NPCs of the developing brains, whose upregulation has been shown to correlate with an increased proliferative potential and hampered neuronal differentiation.
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