Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development.
Notch-like receptors are found in organisms ranging from nematodes to mammals. In Drosophila, Notch plays a key role in cell fate decisions in the early nervous system. In this report we analyse the effects of excess Notch 3 activity in central nervous system (CNS) progenitor cells. A mutated Notch gene encoding the intracellular domain of mouse Notch 3 transcribed from the nestin promoter was expressed in CNS progenitor cells in transgenic mice. This mutation resulted in a phenotypic series of neural tube defects in embryonic day 10.5-12.5 embryos and proved lethal to embryos beyond this age. In the milder phenotype the neural tube displayed a zig-zag morphology and the CNS was slightly enlarged. More severely affected embryos showed a lack of closure of the anterior neural pore, resulting in the externalization of neural tissue and the complete collapse of the third and fourth ventricles. The expanded ventricular zone of the neuroepithelium, a correspondingly enlarged area of nestin expression, and an increase in the number of proliferating cells in the neural tube suggested that these phenotypes resulted from an expanded CNS progenitor cell population. These data provide support in vivo for the notion that Notch activity plays a role in mammalian CNS development and may be required to guide CNS progenitor cells in their choice between continued proliferation or neuronal differentiation.
Lardelli
M
M
Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, Stockholm, Sweden.
Williams
R
R
Mitsiadis
T
T
Lendahl
U
U
D000818:Animals; D002454:Cell Differentiation; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology*; D018398:Homeodomain Proteins / Q000737:chemistry; D007381:Intermediate Filament Proteins / Q000737:chemistry; D060850:LIM-Homeodomain Proteins; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins; D064231:Nestin; D016900:Neurofilament Proteins / Q000737:chemistry; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface / Q000235:genetics*; D051880:Receptors, Notch; D013234:Stem Cells / Q000737:chemistry*; D014157:Transcription Factors
D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; D060850:LIM-Homeodomain Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D016900:Neurofilament Proteins; D011518:Proto-Oncogene Proteins; D000074562:Receptor, Notch4; D011956:Receptors, Cell Surface; D051880:Receptors, Notch; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1; C073572:Notch4 protein, mouse