c- and N-myc regulate neural precursor cell fate, cell cycle, and metabolism to direct cerebellar development.

Abstract

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.

• Authors: Alice Wey, Veronica Martinez Cerdeno, David Pleasure, Paul S Knoepfler
• Journal: Cerebellum (London, England) (Cerebellum) Vol. 9 Issue 4 Pg. 537-47 (Dec 2010) ISSN: 1473-4230 [Electronic] United States
• PMID: 20658325 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Atoh1 protein, mouse
• Basic Helix-Loop-Helix Transcription Factors
• Intermediate Filament Proteins
• NES protein, human
• Nerve Tissue Proteins
• Nes protein, mouse
• Nestin
• Proto-Oncogene Proteins c-myc
• Tubulin
• beta3 tubulin, mouse
• 2',3'-Cyclic-Nucleotide Phosphodiesterases
• Glutamate Decarboxylase
• glutamate decarboxylase 1
• Bromodeoxyuridine

Topics

• 2',3'-Cyclic-Nucleotide Phosphodiesterases (metabolism)
• Age Factors
• Animals
• Animals, Newborn
• Basic Helix-Loop-Helix Transcription Factors (metabolism)
• Brain (cytology, growth & development, metabolism)
• Bromodeoxyuridine (metabolism)
• Cell Cycle (physiology)
• Cerebellum (cytology, growth & development, metabolism)
• Embryo, Mammalian
• Gene Expression Regulation, Developmental (genetics)
• Glutamate Decarboxylase (metabolism)
• Intermediate Filament Proteins (genetics)
• Mice
• Mice, Knockout
• Nerve Tissue Proteins (genetics, metabolism)
• Nestin
• Neural Stem Cells (physiology)
• Proto-Oncogene Proteins c-myc (deficiency, metabolism)
• Tubulin (metabolism)