Neural development is dependent on the function of specificity protein 2 in cell cycle progression

Abstract

SUMMARYFaithful progression through the cell cycle is crucial to the maintenance and developmental potential of stem cells. Here, we demonstrate that neural stem cells (NSCs) and intermediate neural progenitor cells (NPCs) employ a zinc-finger transcription factor specificity protein 2 (Sp2) as a cell cycle regulator in two temporally and spatially distinct progenitor domains. Differential conditional deletion of Sp2 in early embryonic cerebral cortical progenitors, and perinatal olfactory bulb progenitors disrupted transitions through G1, G2 and M phases, whereas DNA synthesis appeared intact. Cell-autonomous function of Sp2 was identified by deletion of Sp2 using mosaic analysis with double markers, which clearly established that conditional Sp2-null NSCs and NPCs are M phase arrested in vivo. Importantly, conditional deletion of Sp2 led to a decline in the generation of NPCs and neurons in the developing and postnatal brains. Our findings implicate Sp2-dependent mechanisms as novel regulators of cell cycle progression, the absence of which disrupts neurogenesis in the embryonic and postnatal brain.

Neural Stem Cells to Cerebral Cortex: Emerging Mechanisms Regulating Progenitor Behavior and Productivity

“…For example, human mutations in mitosis and DNA repair genes can cause microcephaly while sparing most other tissues (Faheem et al, 2015). Cytokinesis, which follows mitosis but is regulated separately, also plays crucial roles in building the cortex, and mutations in cytokinesis genes can also cause malformations, such as microcephaly and microlissencephaly (Harding et al, 2016;Li et al, 2016). While studies of cytokinesis during cortical development have barely begun, tools to study it are rapidly evolving.…”

TransOmic analysis of forebrain sections in Sp2 conditional knockout embryonic mice using IR-MALDESI imaging of lipids and LC-MS/MS label-free proteomics

“…In contrast, the width of embryonic sections examined here typically ranged from 2 to 3 mm. To examine molecular differences in the cerebral cortex of developing mouse brains in which Sp2 was conditionally deleted [3], a sufficient resolution of physiological features in the embryonic forebrain was thus prerequisite. Focus was placed on base-line characterization of rostral forebrain sections for this part of the study as a prelude to comparison of control and Sp2-cKO cortices in these sections.…”

“…Sp2-floxed mice were generated and genotyped as described previously [3] and successively crossed to Emx1 cre mice (Jackson Laboratory, Bar Harbor, ME, USA; catalogue #005628) to generate Emx1 cre :Sp2 F/F mice (Sp2-cKO). Cre -negative embryos were used as littermate controls (WT).…”

“…Absolute ion abundances associated with the peak list were subsequently extracted for each sample from each voxel in the dorsolateral cortex within a 5-ppm mass measurement accuracy window. To account for phenotypical differences in the thickness of the cortex between Sp2-cKO and WT [3], the ion abundances were individually normalized by the number of voxels and low abundant m / z values were excluded from further analysis by introduction of an average ion abundance threshold of 100 a.u. Eight m / z values with more than 15 % of the observations below the threshold value were thus removed from the dataset.…”

“…Sp2-dependent transcription regulates a variety of housekeeping, tissue-specific, developmental, and fundamental cell cycle processes [1, 2]. In a past study, we showed that Sp2 expression is critical for cortical development through regulation of the cell cycle in neural progenitors [3], in part through presumptive regulation of cholesterol metabolism [2]. …”