NeuroD2 is necessary for development and survival of central nervous system neurons.
NeuroD2 is sufficient to induce cell cycle arrest and neurogenic differentiation in nonneuronal cells. To determine whether this bHLH transcription factor was necessary for normal brain development, we used homologous recombination to replace the neuroD2 coding region with a beta-galactosidase reporter gene. The neuroD2 gene expressed the reporter in a subset of neurons in the central nervous system, including in neurons of the neocortex and hippocampus and cerebellum. NeuroD2(-/-) mice showed normal development until about day P14, when they began exhibiting ataxia and failure to thrive. Brain areas that expressed neuroD2 were smaller than normal and showed higher rates of apoptosis. Cerebella of neuroD2-null mice expressed reduced levels of genes encoding proteins that support cerebellar granule cell survival, including brain-derived neurotrophic factor (BDNF). Decreased levels of BDNF and higher rates of apoptosis in cerebellar granule cells of neuroD2(-/-) mice indicate that neuroD2 is necessary for the survival of specific populations of central nervous system neurons in addition to its known effects on cell cycle regulation and neuronal differentiation.
Olson
J M
JM
Clinical Research and Human Biology Divisions and Program in Developmental Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. jolson@fhcrc.org
Asakura
A
A
Snider
L
L
Hawkes
R
R
Strand
A
A
Stoeck
J
J
Hallahan
A
A
Pritchard
J
J
Tapscott
S J
SJ
D000818:Animals; D017209:Apoptosis; D001259:Ataxia; D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis; D002453:Cell Cycle; D002454:Cell Differentiation; D002470:Cell Survival; D002490:Central Nervous System / Q000166:cytology*; D002525:Cerebellar Cortex / Q000166:cytology; D004827:Epilepsy; D005183:Failure to Thrive; D017353:Gene Deletion; D051379:Mice; D008817:Mice, Mutant Strains; D009043:Motor Activity; D009474:Neurons / Q000166:cytology*; D009479:Neuropeptides / Q000235:genetics*; D014018:Tissue Distribution; D014157:Transcription Factors / Q000235:genetics*
D051792:Basic Helix-Loop-Helix Proteins; D019208:Brain-Derived Neurotrophic Factor; D009479:Neuropeptides; D014157:Transcription Factors; C098995:Neurod2 protein, mouse