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Presenilins are required for maintenance of neural stem cells in the developing brain.

Kim WY, Shen J - Mol Neurodegener (2008)

Bottom Line: The length of cell cycle, however, is unchanged in PS cDKO embryos.Expression of Notch target genes, Hes1 and Hes5, is significantly decreased in PS cDKO brains, whereas Dll1 expression is up-regulated, indicating that Notch signaling is effectively blocked by PS inactivation.These findings demonstrate that presenilins are essential for neural progenitor cells to re-enter cell cycle and thus ensure proper expansion of neural progenitor pool during embryonic neural development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA, 02115, USA. jshen@rics.bwh.harvard.edu.

ABSTRACT
The early embryonic lethality of mutant mice bearing germ-line deletions of both presenilin genes precluded the study of their functions in neural development. We therefore employed the Cre-loxP technology to generate presenilin conditional double knockout (PS cDKO) mice, in which expression of both presenilins is inactivated in neural progenitor cells (NPC) or neural stem cells and their derivative neurons and glia beginning at embryonic day 11 (E11). In PS cDKO mice, dividing NPCs labeled by BrdU are decreased in number beginning at E13.5. By E15.5, fewer than 20% of NPCs remain in PS cDKO mice. The depletion of NPCs is accompanied by severe morphological defects and hemorrhages in the PS cDKO embryonic brain. Interkinetic nuclear migration of NPCs is also disrupted in PS cDKO embryos, as evidenced by displacement of S-phase and M-phase nuclei in the ventricular zone of the telencephalon. Furthermore, the depletion of neural progenitor cells in PS cDKO embryos is due to NPCs exiting cell cycle and differentiating into neurons rather than reentering cell cycle between E13.5 and E14.5 following PS inactivation in most NPCs. The length of cell cycle, however, is unchanged in PS cDKO embryos. Expression of Notch target genes, Hes1 and Hes5, is significantly decreased in PS cDKO brains, whereas Dll1 expression is up-regulated, indicating that Notch signaling is effectively blocked by PS inactivation. These findings demonstrate that presenilins are essential for neural progenitor cells to re-enter cell cycle and thus ensure proper expansion of neural progenitor pool during embryonic neural development.

No MeSH data available.


Related in: MedlinePlus

Ectopic localization of S-phase nuclei in the ventricular zone of PS cDKO brains. (A, B) At E13.5, in control brains, the BrdU-positive nuclei are localized in the upper ventricular zone closer to the preplate, whereas in PS cDKO brains, they are distributed more broadly and predominantly in the lower ventricular zone closer to the ventricle, suggesting disrupted interkinetic nuclear migration. (C, D) At E14.5, in PS cDKO brains, the BrdU-positive nuclei are absent in many areas of the ventricular zone and are distributed close to the lateral ventricle. (E) The ventricular zone that contains BrdU-positive cells is divided by 11 bins (15 μm/bin). Bin 1 is the layer closest to the preplate (PP), whereas bin 11 is the layer closest to the lateral ventricle (LV). n = 5 for the controls and n = 6 for PS cDKO embryos. Scale bar: 100 μm in all figures.
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Figure 2: Ectopic localization of S-phase nuclei in the ventricular zone of PS cDKO brains. (A, B) At E13.5, in control brains, the BrdU-positive nuclei are localized in the upper ventricular zone closer to the preplate, whereas in PS cDKO brains, they are distributed more broadly and predominantly in the lower ventricular zone closer to the ventricle, suggesting disrupted interkinetic nuclear migration. (C, D) At E14.5, in PS cDKO brains, the BrdU-positive nuclei are absent in many areas of the ventricular zone and are distributed close to the lateral ventricle. (E) The ventricular zone that contains BrdU-positive cells is divided by 11 bins (15 μm/bin). Bin 1 is the layer closest to the preplate (PP), whereas bin 11 is the layer closest to the lateral ventricle (LV). n = 5 for the controls and n = 6 for PS cDKO embryos. Scale bar: 100 μm in all figures.

Mentions: During the cell cycle neural progenitor cells in the developing forebrain undergo a process termed interkinetic nuclear migration (INM) [28]. We then examined whether inactivation of presenilins affects the INM process. At E12.5 and earlier stages, no difference was observed between PS cDKO and control brains. By E13.5, however, the S-phase nuclei in the mutant mice were detected in abnormal positions; rather than localized in the basal are of the ventricular zone, they are randomly distributed in the ventricular zone and are especially clustered near the ventricle (Figure 2A, B). To quantify the ectopic distribution of the S-phase nuclei, we divided the cortical ventricular zone into 11 bins from the preplate to the ventricle and then counted the number of the S-phase nuclei in each bin (Figure 2E). The quantitative analysis further confirmed the ectopic localization of the S-phase nuclei at this developmental stage. By E14.5, the interkinetic nuclear migration was further disrupted in PS cDKO brains with the S-phase nuclei clustered near the ventricle surface in many places (Figure 2C, D).


Presenilins are required for maintenance of neural stem cells in the developing brain.

Kim WY, Shen J - Mol Neurodegener (2008)

Ectopic localization of S-phase nuclei in the ventricular zone of PS cDKO brains. (A, B) At E13.5, in control brains, the BrdU-positive nuclei are localized in the upper ventricular zone closer to the preplate, whereas in PS cDKO brains, they are distributed more broadly and predominantly in the lower ventricular zone closer to the ventricle, suggesting disrupted interkinetic nuclear migration. (C, D) At E14.5, in PS cDKO brains, the BrdU-positive nuclei are absent in many areas of the ventricular zone and are distributed close to the lateral ventricle. (E) The ventricular zone that contains BrdU-positive cells is divided by 11 bins (15 μm/bin). Bin 1 is the layer closest to the preplate (PP), whereas bin 11 is the layer closest to the lateral ventricle (LV). n = 5 for the controls and n = 6 for PS cDKO embryos. Scale bar: 100 μm in all figures.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2235867&req=5

Figure 2: Ectopic localization of S-phase nuclei in the ventricular zone of PS cDKO brains. (A, B) At E13.5, in control brains, the BrdU-positive nuclei are localized in the upper ventricular zone closer to the preplate, whereas in PS cDKO brains, they are distributed more broadly and predominantly in the lower ventricular zone closer to the ventricle, suggesting disrupted interkinetic nuclear migration. (C, D) At E14.5, in PS cDKO brains, the BrdU-positive nuclei are absent in many areas of the ventricular zone and are distributed close to the lateral ventricle. (E) The ventricular zone that contains BrdU-positive cells is divided by 11 bins (15 μm/bin). Bin 1 is the layer closest to the preplate (PP), whereas bin 11 is the layer closest to the lateral ventricle (LV). n = 5 for the controls and n = 6 for PS cDKO embryos. Scale bar: 100 μm in all figures.
Mentions: During the cell cycle neural progenitor cells in the developing forebrain undergo a process termed interkinetic nuclear migration (INM) [28]. We then examined whether inactivation of presenilins affects the INM process. At E12.5 and earlier stages, no difference was observed between PS cDKO and control brains. By E13.5, however, the S-phase nuclei in the mutant mice were detected in abnormal positions; rather than localized in the basal are of the ventricular zone, they are randomly distributed in the ventricular zone and are especially clustered near the ventricle (Figure 2A, B). To quantify the ectopic distribution of the S-phase nuclei, we divided the cortical ventricular zone into 11 bins from the preplate to the ventricle and then counted the number of the S-phase nuclei in each bin (Figure 2E). The quantitative analysis further confirmed the ectopic localization of the S-phase nuclei at this developmental stage. By E14.5, the interkinetic nuclear migration was further disrupted in PS cDKO brains with the S-phase nuclei clustered near the ventricle surface in many places (Figure 2C, D).

Bottom Line: The length of cell cycle, however, is unchanged in PS cDKO embryos.Expression of Notch target genes, Hes1 and Hes5, is significantly decreased in PS cDKO brains, whereas Dll1 expression is up-regulated, indicating that Notch signaling is effectively blocked by PS inactivation.These findings demonstrate that presenilins are essential for neural progenitor cells to re-enter cell cycle and thus ensure proper expansion of neural progenitor pool during embryonic neural development.

View Article: PubMed Central - HTML - PubMed

Affiliation: Center for Neurologic Diseases, Brigham & Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA, 02115, USA. jshen@rics.bwh.harvard.edu.

ABSTRACT
The early embryonic lethality of mutant mice bearing germ-line deletions of both presenilin genes precluded the study of their functions in neural development. We therefore employed the Cre-loxP technology to generate presenilin conditional double knockout (PS cDKO) mice, in which expression of both presenilins is inactivated in neural progenitor cells (NPC) or neural stem cells and their derivative neurons and glia beginning at embryonic day 11 (E11). In PS cDKO mice, dividing NPCs labeled by BrdU are decreased in number beginning at E13.5. By E15.5, fewer than 20% of NPCs remain in PS cDKO mice. The depletion of NPCs is accompanied by severe morphological defects and hemorrhages in the PS cDKO embryonic brain. Interkinetic nuclear migration of NPCs is also disrupted in PS cDKO embryos, as evidenced by displacement of S-phase and M-phase nuclei in the ventricular zone of the telencephalon. Furthermore, the depletion of neural progenitor cells in PS cDKO embryos is due to NPCs exiting cell cycle and differentiating into neurons rather than reentering cell cycle between E13.5 and E14.5 following PS inactivation in most NPCs. The length of cell cycle, however, is unchanged in PS cDKO embryos. Expression of Notch target genes, Hes1 and Hes5, is significantly decreased in PS cDKO brains, whereas Dll1 expression is up-regulated, indicating that Notch signaling is effectively blocked by PS inactivation. These findings demonstrate that presenilins are essential for neural progenitor cells to re-enter cell cycle and thus ensure proper expansion of neural progenitor pool during embryonic neural development.

No MeSH data available.


Related in: MedlinePlus