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c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development
Separate murine knockout (KO) of either c- or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre causes microcephaly. The cerebellum is particularly affected in the N-myc KO, leading to a strong reduction in cerebellar granule neural progenitors (CGNP) and mature granule neuro...
Autores principales: | , , , |
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Formato: | Texto |
Lenguaje: | English |
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Springer-Verlag
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996535/ https://www.ncbi.nlm.nih.gov/pubmed/20658325 http://dx.doi.org/10.1007/s12311-010-0190-9 |
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author | Wey, Alice Cerdeno, Veronica Martinez Pleasure, David Knoepfler, Paul S. |
author_facet | Wey, Alice Cerdeno, Veronica Martinez Pleasure, David Knoepfler, Paul S. |
author_sort | Wey, Alice |
collection | PubMed |
description | Separate murine knockout (KO) of either c- or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre causes microcephaly. The cerebellum is particularly affected in the N-myc KO, leading to a strong reduction in cerebellar granule neural progenitors (CGNP) and mature granule neurons. In humans, mutation of N-myc also causes microcephaly in Feingold Syndrome. We created a double KO (DKO) of c- and N-myc using nestin-cre, which strongly impairs brain growth, particularly that of the cerebellum. Granule neurons were almost absent from the Myc DKO cerebellum, and other cell types were relatively overrepresented, including astroglia, oligodendrocytes, and Purkinje neurons. These findings are indicative of a profound disruption of cell fate of cerebellar stem and precursors. DKO Purkinje neurons were strikingly lacking in normal arborization. Inhibitory neurons were ectopic and exhibited very abnormal GAD67 staining patterns. Also consistent with altered cell fate, the adult DKO cerebellum still retained a residual external germinal layer (EGL). CGNP in the DKO EGL were almost uniformly NeuN and p27KIP1 positive as well as negative for Math1 and BrdU at the peak of normal cerebellar proliferation at P6. The presence of some mitotic CGNP in the absence of S phase cells suggests a possible arrest in M phase. CGNP and NSC metabolism also was affected by loss of Myc as DKO cells exhibited weak nucleolin staining. Together these findings indicate that c- and N-Myc direct cerebellar development by maintaining CGNP and NSC populations through inhibiting differentiation as well as directing rapid cell cycling and active cellular metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12311-010-0190-9) contains supplementary material, which is available to authorized users. |
format | Text |
id | pubmed-2996535 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Springer-Verlag |
record_format | MEDLINE/PubMed |
spelling | pubmed-29965352011-01-04 c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development Wey, Alice Cerdeno, Veronica Martinez Pleasure, David Knoepfler, Paul S. Cerebellum Article Separate murine knockout (KO) of either c- or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre causes microcephaly. The cerebellum is particularly affected in the N-myc KO, leading to a strong reduction in cerebellar granule neural progenitors (CGNP) and mature granule neurons. In humans, mutation of N-myc also causes microcephaly in Feingold Syndrome. We created a double KO (DKO) of c- and N-myc using nestin-cre, which strongly impairs brain growth, particularly that of the cerebellum. Granule neurons were almost absent from the Myc DKO cerebellum, and other cell types were relatively overrepresented, including astroglia, oligodendrocytes, and Purkinje neurons. These findings are indicative of a profound disruption of cell fate of cerebellar stem and precursors. DKO Purkinje neurons were strikingly lacking in normal arborization. Inhibitory neurons were ectopic and exhibited very abnormal GAD67 staining patterns. Also consistent with altered cell fate, the adult DKO cerebellum still retained a residual external germinal layer (EGL). CGNP in the DKO EGL were almost uniformly NeuN and p27KIP1 positive as well as negative for Math1 and BrdU at the peak of normal cerebellar proliferation at P6. The presence of some mitotic CGNP in the absence of S phase cells suggests a possible arrest in M phase. CGNP and NSC metabolism also was affected by loss of Myc as DKO cells exhibited weak nucleolin staining. Together these findings indicate that c- and N-Myc direct cerebellar development by maintaining CGNP and NSC populations through inhibiting differentiation as well as directing rapid cell cycling and active cellular metabolism. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12311-010-0190-9) contains supplementary material, which is available to authorized users. Springer-Verlag 2010-07-25 2010 /pmc/articles/PMC2996535/ /pubmed/20658325 http://dx.doi.org/10.1007/s12311-010-0190-9 Text en © The Author(s) 2010 https://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Article Wey, Alice Cerdeno, Veronica Martinez Pleasure, David Knoepfler, Paul S. c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development |
title | c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development |
title_full | c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development |
title_fullStr | c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development |
title_full_unstemmed | c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development |
title_short | c- and N-myc Regulate Neural Precursor Cell Fate, Cell Cycle, and Metabolism to Direct Cerebellar Development |
title_sort | c- and n-myc regulate neural precursor cell fate, cell cycle, and metabolism to direct cerebellar development |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2996535/ https://www.ncbi.nlm.nih.gov/pubmed/20658325 http://dx.doi.org/10.1007/s12311-010-0190-9 |
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