Neuronal basic helix-loop-helix proteins (NEX and BETA2/Neuro D) regulate terminal granule cell differentiation in the hippocampus.
The transcription factors neuronal helix-loop-helix protein (NEX)/mammalian atonal homolog 2 (Math-2), BETA2/neuronal determination factor (NeuroD), and NeuroD-related factor (NDRF)/NeuroD2 comprise a family of Drosophila atonal-related basic helix-loop-helix (bHLH) proteins with highly overlapping expression in the developing forebrain. The ability of BETA2/NeuroD and NDRF to convert ectodermal cells into neurons after mRNA injection into Xenopus oocytes suggested a role in specifying neuronal cell fate. However, neuronal bHLH genes are largely transcribed in CNS neurons, which are fully committed. Here we analyze a defect in mice lacking BETA2/NeuroD, and in NEX*BETA2/NeuroD double mutants, demonstrating that bHLH proteins are required in vivo for terminal neuronal differentiation. Most strikingly, presumptive granule cells of the dentate gyrus are generated but fail to mature, lack normal sodium currents, and show little dendritic arborization. Long-term hippocampal slice cultures demonstrate secondary alterations of entorhinal and commissural/associational projections. The primary developmental arrest appears to be restricted to granule cells in which an autoregulatory system involving all three neuronal bHLH genes has failed.
Schwab
M H
MH
Zentrum für Molekulare Biologie, University of Heidelberg, D-69120 Heidelberg, Germany.
Bartholomae
A
A
Heimrich
B
B
Feldmeyer
D
D
Druffel-Augustin
S
S
Goebbels
S
S
Naya
F J
FJ
Zhao
S
S
Frotscher
M
M
Tsai
M J
MJ
Nave
K A
KA
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000502:physiology; D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal / Q000032:analysis; D002454:Cell Differentiation / Q000502:physiology; D018891:Dentate Gyrus / Q000166:cytology* / Q000254:growth & development; D016326:Extracellular Matrix Proteins / Q000032:analysis; D018507:Gene Expression Regulation, Developmental; D018257:Helix-Loop-Helix Motifs / Q000235:genetics*; D020287:In Situ Nick-End Labeling; D019426:Integrases / Q000378:metabolism; D019394:Ki-67 Antigen / Q000032:analysis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009474:Neurons / Q000737:chemistry / Q000166:cytology* / Q000201:enzymology; D018408:Patch-Clamp Techniques; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D015533:Transcriptional Activation / Q000502:physiology; D014764:Viral Proteins
D051792:Basic Helix-Loop-Helix Proteins; D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D019426:Integrases; D019394:Ki-67 Antigen; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D014764:Viral Proteins; C110701:Neurod6 protein, mouse; C093564:Neurogenic differentiation factor 1; C045073:Cre recombinase