Abstract
The Snail transcription factor regulates diverse aspects of stem cell biology in organisms ranging from Drosophila to mammals. Here we have asked whether it regulates the biology of neural precursor cells (NPCs) in the forebrain of postnatal and adult mice, taking advantage of a mouse containing a floxed Snail allele (Snailfl/fl mice). We show that when Snail is inducibly ablated in the embryonic cortex, this has long-term consequences for cortical organization. In particular, when Snailfl/fl mice are crossed to Nestin-cre mice that express Cre recombinase in embryonic neural precursors, this causes inducible ablation of Snail expression throughout the postnatal cortex. This loss of Snail causes a decrease in proliferation of neonatal cortical neural precursors and mislocalization and misspecification of cortical neurons. Moreover, these precursor phenotypes persist into adulthood. Adult neural precursor cell proliferation is decreased in the forebrain subventricular zone and in the hippocampal dentate gyrus, and this is coincident with a decrease in the number of adult-born olfactory and hippocampal neurons. Thus, Snail is a key regulator of the numbers of neural precursors and newborn neurons throughout life.
Highlights
Radial neural precursor cells of the developing cortex must proliferate, differentiate and in some cases, undergo apoptosis in order to populate the postnatal cortex with the appropriate numbers and types of cells to generate cortical neural circuitry [1]
While most of these multipotent precursor cells differentiate into neurons and glia, a subset fulfill the criteria for bona fide stem cells, since they persist as a subpopulation of neural stem cells in the adult forebrain subventricular zone (SVZ) niche [2]
We recently demonstrated that acute shRNA-mediated knockdown of Snail in embryonic cortical precursors led to a decrease in numbers of neural precursors and newborn neurons that was due to increased apoptosis and decreased proliferation [20]
Summary
Radial neural precursor cells of the developing cortex must proliferate, differentiate and in some cases, undergo apoptosis in order to populate the postnatal cortex with the appropriate numbers and types of cells to generate cortical neural circuitry [1]. Immunostaining of coronal cortical sections from Snailfl/fl mice negative for the nestin-cre transgene showed that the majority of BrdU-positive cells were located in layers II-IV (Figure 3B,C). While approximately 18% of BrdU-positive cells in the control SVZ were Ki67-positive, this number was significantly decreased in Snailfl/fl;nestin-cre cortices (Figure 3F).
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